Categories of recreational drugs

Worldwide, a large number of substances are used recreationally, some legally and some not (Table 1) (39). Two types of drug dependence may occur: (1) psychic dependence (addiction) leads to craving and drug-seeking behavior; (2) physical dependence produces somatic withdrawal symptoms. Tolerance refers to the need to increase the dose of a substance to achieve the desired effect or to prevent withdrawal. Abuse refers to recreational use of an agent despite evidence of its harmfulness.

Table 1. Categories of Recreational Drugs

• Opioids • Psychostimulants • Sedatives and hypnotics • Cannabis • Hallucinogens • Inhalants • Phencyclidine • Anticholinergics • Ethanol • Tobacco

This article deals with those drugs—other than alcohol, tobacco, and caffeine—that are most often used recreationally in North America and Europe. The prevalence of illicit drug use, varying from region to region and from decade to decade, can be only crudely estimated from household surveys and hospital statistics. For example, the U.S. Department of Health and Human Service’s National Survey on Drug Use and Health reported that in 2005 20.1% of Americans aged 18 to 25 years had used an illicit drug during the past month. In 2016, a national epidemiological survey of American adults reported a 9.9% lifetime prevalence of DSM-5 drug use disorder (not including ethanol or tobacco) (119). Also, in 2016, the U.S. Surgeon General released “Facing Addiction in America,” the first ever Surgeon General’s report on substance use and addiction. The aim of the report was to shift the perception of addiction as “a moral failing” to “a chronic brain disease.” The report covers the neurobiology of addiction as well as proposals for prevention, treatment, and support services (30; U.S. Department of Health and Human Services Office of the Surgeon General 2016).

In reviewing the clinical features of individual agents, it is important to recognize that drug abusers do not usually limit themselves to a single agent and might be simultaneously intoxicated by drug combinations or even intoxicated with one agent while withdrawing from another.

Categories of drug use

Opioids. Opioids include agonists, antagonists, and mixed agonist-antagonists (Table 2). In the past, the agent most often abused was heroin, classified by the United States Food and Drug Administration (FDA) as Schedule I (high potential for abuse, no accepted medical use). In recent decades, the U.S. and other countries have experienced an upsurge in the use of prescription opioids--especially hydromorphone, methadone, and products containing oxycodone and hydrocodone--in treating chronic, non-cancer pain (130; 314). This trend was soon followed by an epidemic of recreational use of these products (72; 131; 318). Especially popular was oxycodone (misleadingly marketed by Purdue Pharmacy as minimally addictive Oxy-Contin) (306). In California, a mixture of hydrocodone and acetaminophen (brand name “Narco”) became available as a street drug (13). In contrast to past epidemics of heroin use, recreational prescription opioid users in the United States tended to be white, non-urban, and young men and women (165; 207; 323). During this period, heroin use also surged, with the increase mostly accounted for by non-medical users of prescription opioids who found heroin cheaper and easier to obtain (57; 61; 132). From 2000 to 2015 the annual number of opioid overdoses (prescription plus illicit opioids) in the U.S. more than tripled (225; 280). Of 33,091 drug overdose deaths in the United States during 2015, 63% involved an opioid. During 2016, the number of overdose deaths rose to 63,632 (66% opioid-related), and during 2017 it rose to 72,306 (84% opioid-related) (270; 52).

Whereas the early years of the opioid epidemic were marked by transition from prescription drugs to heroin, recent years have seen the emergence of “designer opioids,” (14; 105; 157; 174; 84). Dozens of different fentanyl analogs (eg, sufentanil, alfentanil, remifentanil, carfentanil) are available throughout the United States (148). They are often mixed with other drugs, including other opioids (up to 64%), cocaine (up to 65%), cannabinoids (up to 50%); amphetamines (up to 40%), ethanol (up to 23%), benzodiazepines (up to 52%), barbiturates (up to 27%), and antidepressants (up to 49%) (105). Novel non-fentanyl opioids (eg, AH-7921, MT-45, and “U-series” drugs—U-47700, U-48800, and U-49900) are more often purchased directly. Fentanyl, fentanyl analogs, and other designer opioids are sold in powder, tablet, or liquid forms and can be swallowed, snorted, smoked, injected, administered sublingually or rectally, or vaped with an electronic cigarette (157). Fentanyl can be extracted from patches for injection, ingestion, or inhalation (158). Of 60,674 fatal opioid overdoses in the United States during 2017, 3295 involved methadone (5%), 14,958 involved natural and semisynthetic opioids (24%), 15,958 involved heroin (26%), and 29,406 involved fentanyl, fentanyl analogs, and other novel designer opioids. Fentanyl has 50 to 100 times the potency of morphine. Carfentanyl’s potency is 10,000 time that of morphine.

It is estimated that 20% of patients prescribed opioids for chronic pain become long-term users (272).

From 2017 to 2018, overall U.S. opioid deaths decreased 4.6%, but the decreases occurred in prescription opioid deaths with no decrease in deaths involving illicit opioids. Two-thirds of opioid deaths during 2018 involved fentanyl analogs and non-fentanyl-related synthetic opioids (113). Fentanyl and fentanyl analogs are often present in drug samples sold as cocaine (82; 235).

During this period deaths co-occurring with benzodiazepine decreased by 5.7%, but deaths co-occurring with methamphetamine increased by 14.6% (113). Increasing use of opioids combined with psychostimulants (taken, variably, for enhancement of the high or compensation for undesired effects of the opioid) is considered the “fourth wave” (after prescription opioids, heroin, and synthetic opioids) of an ever-changing opioid crisis (62; 206; 235; 315).

Opioid overdose is a major contributor to declining life expectancy in the United States (133). From 1999 to 2018, opioid overdose accounted for nearly 450,0000 deaths in the U.S. and it is estimated that currently 1 American dies every 11 minutes from opioid overdose (147). The situation became even worse during the COVID-19 pandemic, reflecting a bidirectional association. Opioid use disorder carries risk for contracting and spreading COVID-19 and opioids are immunosuppressant. Lockdown became a barrier to care for individuals with opioid use disorder (176; 199).

In 2014, a position paper from the American Academy of Neurology citing lack of evidence that opioid analgesics are effective in treating non-cancer pain as well as the risk of dependence and overdose provided guidelines for prescribing opioids to non-cancer patients (99). In 2015 President Barack Obama announced a national initiative to curb the opioid epidemic, noting that 4 of 5 American heroin users had started with prescription opioids (209). The long-term efficacy of opioids for non-cancer pain is questionable; in fact, not only is chronic use often ineffective but it can create a state of hyperalgesia (204; 212). In 2016, the U.S. Centers for Disease Control and Prevention published practice guidelines for opioid use, and many states increased regulation of opioid prescriptions by physicians (34; 103; 200; 316; 169; 267; 318). Pharmaceutical companies responded to the prescription opioid epidemic by marketing “abuse deterrent” formulations, such as adding the mu-receptor antagonist naloxone to pills, rendering them ineffective if injected. Other strategies include addition of an agent that causes aversive symptoms if injected or manufacturing oral tablets that are very difficult to crush (10; 200; 318; 244).

Escalating opioid overdose death has resulted in expanded access to naloxone and to syringe service programs (210). Naloxone is currently available over-the-counter as a nasal spray or an auto-injector. Unfortunately, whereas a lifesaving dose of naloxone in 2009 cost $1, a nasal spray in 2018 cost $150, and the auto-injector costs $4500 (281).

Loperamide, an over-the-counter anti-diarrheal with opioid agonist properties, is used to relieve opioid withdrawal as well as to produce euphoria. In addition to CNS depression, users are at risk for fatal cardiac arrhythmias (85; 307).

Persons prescribed opioids are often additionally prescribed benzodiazepines, and in 2016, responding to escalating death rates in people taking both agents, the FDA directed that a black box warning appear on the labels of all benzodiazepine and opioid products (238; 192; 105).

In Eastern Europe, a designer opioid, desomorphine, has become increasingly popular. Called Krokodil for the green-black skin lesions found on users, the injectable drug is made by cooking crushed codeine pills with household hydrocarbons such as paint thinner and gasoline (05; 250). Krokodil use spread into Western Europe, and by 2018 official cases were reported in Arizona, Missouri, Cleveland, and New York. In the United States, desomorphine, which binds to mu-, delta-, and kappa-opioid receptors, is a schedule 1 drug (04).

Kratom, obtained from a Southeast Asian tree, contains numerous alkaloids, of which mitragynine has opioid-like as well as serotonergic and noradrenergic effects. Kratom leaves can be chewed, brewed as teas, ingested as capsules, or smoked. Despite warnings by the DEA, kratom use in the U.S. was legal in most states as of 2016, and over the past several years, its popularity has steadily increased. Kratom produces stimulant effects at low doses and opioid effects at higher doses. Adverse effects include anxiety, aggression, palpitations, and seizures. Kratom combined with O-desmethyltramadol (a tramadol metabolite) is marketed as “krypton.” Routine toxicologic screens do not detect kratom. Mitragynine is addictive, and withdrawal symptoms are similar to those of opioids (250). Fatal overdose has followed ingestion of mitragynine combined with tramadol or with the decongestant propylhexedrine (250; 11; 276; 109; 66).

Public advocacy for using kratom to treat opioid withdrawal or opioid use disorder lacks supportive evidence (266).

At desired levels of intoxication, opioid agonists produce drowsy euphoria, analgesia, cough suppression, miosis, and often nausea, vomiting, sweating, pruritus, hypothermia, postural hypotension, constipation, and decreased libido. Injected or smoked, heroin produces a brief ecstatic “rush” followed usually by relaxed euphoria. Overdose causes the triad of coma, respiratory depression, and pinpoint (but reactive) pupils. In adults with respiratory depression, treatment includes ventilatory support and naloxone, 2 mg intravenously repeated as needed up to 20 mg; smaller doses are given when respirations are normal. An intranasal preparation is available for first responders (148). Naloxone is short-acting, so patients receiving it require careful observation. Fentanyl, fentanyl analogs, and novel synthetic opioids require larger and often repeated doses of naloxone to reverse respiratory depression (60).

Table 2. Commonly Used Opioids

Agonist
	• Camphorated tincture of opium (paregoric) • Morphine (morphine sulfate injection) • Heroin • Methadone • Fentanyl • Hydromorphone • Codeine • Oxycodone • Hydrocodone • Dihydrocodeine (in mixtures) • Tramadol • Meperidine • Propoxyphene • Oxymorphone • Tapentadol
Antagonist
	• Naloxone • Naltrexone
Mixed agonist-antagonist
	• Pentazocine • Butorphanol • Buprenorphine • Nalbuphine

Opioid withdrawal produces irritability, lacrimation, rhinorrhea, sweating, yawning, mydriasis, myalgia, muscle spasms, piloerection, nausea, vomiting, abdominal cramps, fever, hot flashes, tachycardia, hypertension, orgasm, and intense craving. In adults, seizures and delirium are not features of opioid withdrawal, which might be compared to a severe flu-like illness. Infrequently, however, opioid withdrawal can cause severe fluid loss and electrolyte abnormalities, hemodynamic instability, and death. Symptoms can usually be treated (or prevented) with methadone 10 to 30 mg once or twice daily, titrated upward as needed. Alternative opioids include the mu-receptor partial agonist buprenorphine. Evidence supports the benefit of the weak mu-receptor agonist tramadol, but as of 2021 it had not been approved for this purpose by the U.S. Food and Drug Administration and it does have abuse potential (121). The alpha-2-adrenergic receptor agonists clonidine, lofexidine, guanfacine, and tizanidine suppress norepinephrine-mediated sympathetic symptoms but do not reduce craving and can produce hypotension (287).

In newborns, untreated opioid withdrawal is severe, sometimes with seizures or myoclonus, and if untreated can be fatal; treatment is with titrated doses of an opioid (124). Clinicians favoring morphine over methadone cite morphine’s easier dose adjustment and methadone’s reported association with prolonged QT interval and with somatic and brain growth reduction and delayed encephalopathy (240). In a comparative trial, the duration of treatment for neonatal opioid abstinence syndrome was shorter with buprenorphine than with morphine (171). As a result of the current opioid abuse epidemic, the number of newborns developing neonatal abstinence syndrome has increased dramatically (Patrick et al 2015; 299; 306).

Psychostimulants. Psychostimulants include a number of licit and illicit agents, of which cocaine, methamphetamine, and methylenedioxymethamphetamine (MDMA, “ecstasy,” “Molly”) are the principal drugs of abuse (Table 3). In 2008, 25 million people worldwide abused amphetamines and 14 million abused cocaine. In a 2018 national survey, 1.9 million Americans aged 12 years or older reported past year methamphetamine use, and 1.1 million met diagnostic criteria for methamphetamine use disorder (ie, dependence) (Substance Abuse and Mental Health Services Administration 2017). Methamphetamine resurgence is linked to the opioid epidemic; methamphetamine use among people with opioid use disorder increased from 18.8% in 2011 to 34.2% in 2017, and compared to previous years, an increasing percentage of users were injecting the drug parenterally (152; 49; 224). In 2017, among 70,237 overdose deaths in the United States, 23,139 (33%) involved cocaine, other psychostimulants, or both. Nearly three fourths of cocaine-related and one half of other psychostimulant-related overdose deaths additionally involved an opioid (156).

Table 3. Commonly Used Psychostimulants

• Dextroamphetamine • Methamphetamine • Ephedrine • Pseudoephedrine • Methylphenidate • Phenmetrazine • Phentermine • Methylenedioxymethamphetamine (MDMA, “ecstasy,” “Molly”) • Cocaine • Cathinone, methcathinone • Modafinil

Cocaine (which, unlike other psychostimulants, is also a local anesthetic) is an alkaloid present in the South American plant Erythroxylon coca. Most often encountered as an urban street drug, cocaine is sniffed, injected, or, as alkaloidal “crack”, smoked. Methamphetamine (“speed”), easily manufactured from commercially available pseudoephedrine, is more popular in the Midwestern and Western United States and in rural areas, where it is injected or, as “ice,” smoked. MDMA, usually taken orally, is popular on college campuses and at “rave” dance parties.

Injected or smoked cocaine or methamphetamine produces a rush subjectively different from that of opioids. Repeated use produces stereotypic activity progressing to bruxism or other dyskinesias and paranoia progressing to hallucinatory psychosis. Overdose causes delirium, tachycardia, hypertensive crisis, malignant hyperthermia, cardiac arrhythmia, myoclonus, seizures, myoglobinuria, shock, coma, and death (129; 205). Treatment includes sedation with benzodiazepines, oxygen, bicarbonate for acidosis, anticonvulsants, cooling, blood pressure control (preferably with an alpha blocker or direct vasodilator), respiratory and blood pressure support, and cardiac monitoring. (In many emergency departments, methamphetamine toxicity is treated with neuroleptics, especially haloperidol; such an approach is controversial, especially regarding evidence from animal studies that the combination of methamphetamine and haloperidol is neurotoxic.)

MDMA overdose, in the setting of frenetic dancing over many hours, carries a particular risk for both hyperthermia and hyponatremia, either of which can be fatal.

In North America and Europe there has been a sharp rise in misuse of prescription stimulant medications, especially methylphenidate (Ritalin) and amphetamine compounds (Adderall). College students use stimulants both for getting a “high” and for perceived cognitive enhancement (although use of these medications appears to be negatively associated with academic performance) (325).

Khat, a shrub indigenous to the Arabian Peninsula and East Africa, contains cathinone, a beta-keto analog of amphetamine. Khat leaves are chewed in that part of the world for their stimulant properties. Designer psychostimulants derived from cathinone are widely available in Europe and North America, purchased through the Internet as “legal highs” (92; 110). Collectively marketed as “bath salts,” available compounds include methcathinone (ephedrone), mephedrone, methylone, and methylenedioxypyrovalerone (MDPV, “Slam,” “Ivory Wave,” “Cloud 9,” “Zoom,” “”Vanilla Sky,” “Bliss”), 4-methyl-methcathinone (4-MMC, “Drone,” “Meow Meow”), 3,4-methylenedioxy-N-methylcathinone (MDMC, M1), 4-methylpentedrone (4-MPD), and eutylone (215; 250; 09; 51; 173). An analogue of MDPV, alpha-pyrrolidinovalerophenome (alpha-PVP), is marketed as “flakka” or “gravel” (168; 236). Although most synthetic cathinones are amphetamine-like in their actions, MDPV and alpha-PVP are cocaine-like in blocking dopamine and norepinephrine reuptake. Numerous fatalities have been reported (157; 178).

Methylenedioxyaminoindane (MDA-1) is a designer analogue of MDMA (106).

Benzylpiperazine is one of several designer analogs of the antihelminth piperazine. Often marketed as “legal ecstasy,” they are serotonergic and, like MDMA, have stimulant effects at low doses and hallucinogenic effects at high doses (263; 275). Combinations of synthetic piperazines are sold as “Molly” (161; 250).

Case reports describe dependence on the nonamphetamine psychostimulant modafinil (172). Reports also describe dependence on the beta-adrenergic agonist and vasopressor mephentermine (117).

Sedatives and hypnotics. Sedative drugs include barbiturates, benzodiazepines, and miscellaneous agents (Table 4). Recreational use is usually oral, with desired effects (euphoria, drowsiness), overdose (coma, respiratory depression), and withdrawal symptoms (tremor, seizures, delirium tremens) resembling what is seen with ethanol.

Benzodiazepines have less abuse potential than barbiturates and are less likely to depress respiration. When taken with opioids or ethanol, however, their margin of safety is considerably reduced. Prescription opioids combined with benzodiazepines--especially alprazolam and diazepam--have been responsible for a large percentage of overdose fatalities in the current epidemic of opioid abuse (146).

“Designer benzodiazepines” began appearing early in the 21st Century. It is estimated that worldwide over 3000 such compounds have been synthesized. In the United States from 2014 to 2017, reported exposures to designer benzodiazepines increased by 330% (50). Reasons for their growing popularity are speculative and include self-treatment of anxiety or insomnia and countering the unpleasant effects of other drugs such as psychostimulants and hallucinogens. Biological half-lives of these agents vary widely, and they can be difficult to detect using standard assays (216).

Table 4. Commonly Used Sedatives and Hypnotics

Barbiturates
	• Phenobarbital • Amobarbital • Secobarbital • Pentobarbital • Butalbital
Benzodiazepines
	• Alprazolam • Chlordiazepoxide • Diazepam • Lorazepam • Oxazepam • Temazepam • Triazolam • Clonazepam • Midazolam
Miscellaneous
	• Buspirone • Chloral hydrate • Ethchlorvynol • Glutethimide • Hydroxyzine • Meprobamate • Methaqualone (no longer produced in the United States) • Paraldehyde • Zolpidem • Zaleplon • Gamma-hydroxybutyric acid

Gamma-hydroxybutyric acid (GHB) is a popular euphoriant at “rave” parties, as are 2 of its precursors, gamma-butyrolactone and 1,4-butanediol (283). Often taken with ethanol, these agents are notorious as “date-rape” drugs. Overdose can cause sedation and respiratory depression or delirium and coma. Withdrawal signs resemble those of other sedatives or ethanol (328).

Numerous case reports describe gabapentin abuse, dependence, and withdrawal. Some users believe gabapentin enhances opioid effects; some believe it dampens cocaine withdrawal symptoms, which include tremor, sweating, tachycardia, hypertension, agitation, hallucinations, and seizures. In 1 report, gabapentin misuse occurred concomitantly with an opioid (45%), benzodiazepine (39%), ethanol (24%), or cocaine (24%) (46). Also misused is the gabapentinoid pregabalin (89). Benzodiazepines do not seem to control symptoms of gabapentin withdrawal (213).

Cannabis. The hemp plant Cannabis sativa contains more than 100 cannabinoid compounds, of which delta-9-tetrahydrocannabinol (delta-9-THC) is the principal psychoactive ingredient. Marijuana consists of cut tops and leaves of the plant. Hashish consists of the plant resin, which contains the highest concentrations of delta-9-THC (123). Marijuana or hashish can be smoked or ingested. “Dabs” refers to concentrated hash oil obtained by butane extraction of delta-9-THC from the cannabis plant. The concentrate is heated, vaporized, and inhaled, often using e-cigarette devices (189; 115).

In the brain, delta-9-THC acts at stereospecific receptors, natural ligands of which are called endocannabinoids (23). Numerous synthetic agonists and antagonists, designed by pharmaceutical companies for research purposes, are now available on the Internet for recreational use. Marketed as “Spice” or “K2,” these products are often far more potent than delta-9-THC (269; 42; 90; 74). Synthetic cannabinoids can be ingested or insufflated, but most users smoke plant material (itself often psychoactive) laced with cannabinoid (214; 302). K2 is now the second most popular illicit drug (after marijuana) among United States high school seniors (151; 162).

In the United States, pharmacological preparations of delta-9-THC (dronabinol) and a synthetic analogue (nabilone) are FDA-approved for treating nausea in patients receiving chemotherapy and wasting in patients with AIDS.

Medical marijuana laws authorize cannabis preparations (usually smoked marijuana) for a variety of disorders, including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, muscular dystrophy, fibromyalgia, and seizures. By 2021, 36 states and Washington D.C. had passed medical marijuana laws, and 15 states and Washington D.C. had legalized recreational marijuana. Reflecting societal permissiveness, between 2002 and 2013 past-year prevalence of marijuana use in the United States increased from 4.1% to 9.5%, and prevalence of DSM-V “marijuana use disorder” (a continuum of dependence severity) rose from 1.5% to 2.9% (134). During 2015, 22.2 million Americans were current marijuana users, and 2.6 million persons aged 12 years or older used cannabis for the first time--7100 new users each day (54). During 2018, 10.5% of Americans aged over17 years reported using marijuana in the past month. Not surprisingly, use is highest in states with legalized recreational marijuana (114). From 1995 to 2015, the average content of cannabis increased from 4% to 12%; with legalization of recreational use, potency has run as high as 30% (07).

A 2014 systematic review from the American Academy of Neurology found evidence for efficacy of oral cannabis extracts containing combinations of delta-9-THC and the non-psychoactive cannabinoid cannabidiol (nabiximols) in treating spasticity, central pain, painful spasms, or urinary frequency in patients with multiple sclerosis (251; 300). Oral cannabis extracts are probably ineffective in treating tremor and levodopa-induced dyskinesias; evidence is lacking for benefit in Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy (140; 170). Class I evidence for a benefit of smoked marijuana in any neurologic condition is similarly lacking (29; 194; 91; 327; 31). In 2016, the DEA, citing the FDA’s inability to find scientific evidence for either safety or benefit, reaffirmed its classification of marijuana as a “Schedule I” drug. Physicians “aiding and abetting” a patient’s procurement of marijuana will thus be violating the federal Controlled Substance Act as well as placing themselves in tenuous liability situations.

Epidemiologic evidence suggests that access to medical marijuana correlates with a decrease in opioid use (226).

Although animal studies demonstrated that delta-9-THC reduced the effective analgesic dose of morphine, human studies failed to demonstrate a comparable “opioid-sparing effect” (185).

Three randomized placebo-controlled trials reported benefit of cannabidiol (Epidiolex), a nonpsychoactive cannabinoid compound, in the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome (08; 296; 79; 108). These studies did not extend beyond 12 to 16 weeks. In an open label, 4-year trial of cannabidiol in children with various kinds of refractory epilepsy, cannabidiol appeared to reduce seizure frequency in 27% of patients, but 81% had adverse side-effects, “serious” in 23% (265).

Cannabidiol is now FDA-approved and carries Schedule 5 classification. Preclinical disease models suggest potential benefit for cannabidiol in treating chronic pain, cardiovascular disease, inflammation, autoimmunity, neurodegenerative disorders, cancer, and opioid addiction (309; 231). A randomized controlled trial found that cannabidiol reduced cue-induced craving in abstinent heroin users (142).

Cannabidiol and hemp oils, derived from Cannabis sativa with low delta-9-THC content, are available in dozens of products sold as dietary supplements.

Smoked marijuana produces relaxed euphoria, disinhibition, depersonalization, subjective time-slowing, conjunctival injection, tachycardia, and postural hypotension. Peak effects of THC are reached within a few minutes of smoking marijuana; peak effects following marijuana ingestion are reached after 1 to 3 hours. Several THC metabolites are pharmacologically active. High doses can cause agitation and hallucinatory psychosis, but fatal overdose has not been documented. Withdrawal is usually mild, with jitteriness, sleep difficulty, or headache, but psychic dependence can be marked (293). The lifetime dependence risk in marijuana users is 9%, but doubles for those who begin use before the age of 17 (compared to 32% for nicotine, 23% for heroin, 17% for cocaine, and 15% for ethanol) (29; 164). Although animals are less inclined to self-administer THC than opioids or psychostimulants, rodent and primate models document the dependence liability of cannabinoids (234).

Widespread legalization of marijuana has been accompanied by numerous reports of unintentional exposure in children, including cannabis resin, cookies, beverages, joints, medical cannabis, passive smoke, candies, and hemp oil (253; 321). Lethargy and ataxia were the most common symptoms, but some had respiratory depression requiring intubation.

Synthetic cannabinoids (“Spice,” “K2,” “Kush,” “Black Mamba,” “Bombay Blue,” “fake weed,” “Mojo,” “Cloud 9,” “Skunk,” “Joker,” “Dream,” “Crazy Clown,” “Syn,” “Haze,” “Dragon Spice”), which are up to 200 times more potent than delta-9-THC, frequently produce serious adverse effects, including psychosis, hallucinations, self-mutilation, cardiac arrhythmia, myocardial infarction, vertigo, hypertension, protracted vomiting, convulsive seizures, acute kidney injury, stroke, and death (214; 268; 273; 302; 308; 63; 67; 93; 257; 292; 12; 35; 181; 237; 293). In New York City, an outbreak of “zombie-like” behavior was caused by the synthetic cannabinoid AMB-FUBINACA (01). Similarly, withdrawal symptoms are more severe than with marijuana, and dependence liability is greater (218). Synthetic cannabinoids are not identified in toxicology screens, and there is no antidote for overdose (214).

Among the cannabinoid compounds of Cannabis sativa is delta-8-THC, which, like delta-9-THC, is psychoactive but is present in only minute amounts. During 2020, extracts of delta-8-THC became increasingly popular as recreational drugs in areas where marijuana is illegal. Products include joints, blunts, gummy bears, vaping devices, and tinctures (256).

A Cochrane review of 21 randomized controlled trials of pharmacotherapies for cannabis dependence found no or incomplete evidence of benefit in any study (222).

Hallucinogens. Dozens of hallucinogenic plants are used recreationally or ritualistically around the world. In the United States, the most popular substances—referred to as “psychedelics” or “serotonergic hallucinogens”—are mescaline from peyote cactus, psilocin and psilocybin from mushrooms, dimethyltryptamine (DMT) in ayahuasca, and the synthetic compound lysergic acid diethylamide (LSD) (303; 221; 94; 118; 19). Increasingly popular is the herb Salvia divinorum, which contains the kappa opioid receptor agonist salvinorin A (249; 250; 245). Numerous “designer” hallucinogens are available with such street names as “Fly” and “Bromodragonfly” (139). Piperazine drugs such as N-benzylpiperazine (BZP) have both stimulant and hallucinogenic properties. “2C drugs” are phenylethylamines with hallucinogenic properties, often sold as “LSD” on blotting paper, but also available as tablets or liquid preparations. An N-2 methoxybenzyl-substituted class of 2C agents is referred to as NBOMe or N-bomb (177; 322; 334).

Benzydamine is a nonsteroidal antiinflammatory agent sold without prescription as a mouthwash. When it is used orally, serotonergic properties can cause hallucinations and recreational use is described (56).

Acute effects following oral ingestion are somatic (dizziness, paresthesias, tremor), psychic (depersonalization, altered mood), and perceptual (distortion and hallucinations—usually formed and vivid). Unintended effects include paranoia and panic, and high doses can cause hypertension, seizures, and stupor, but fatalities are usually the result of accidents or suicide. Fatal overdose is described with NBOMe agents (177). “Flashbacks” consist of the spontaneous reappearance of drug symptoms days or weeks after use.

Psychedelic agents do not lead to dependence or addiction. Studies are currently assessing their possible benefit in treating pain and depression in cancer patients as well as in the treatment of alcoholism and tobacco addiction (75; 107).

Ibogaine, a hallucinogenic drug derived from an African shrub, Tabernanthe iboga, is used locally in religious ceremonies. Anecdotal reports suggest benefit in treating opioid or ethanol dependence but the drug can cause fatal cardiotoxicity. Studies are in progress to develop a nontoxic analog (47).

Inhalants. A wide variety of commercial products are sniffed or huffed, especially by adolescents, to achieve euphoria similar to ethanol intoxication (Table 5). Substances include, variably, halogenated, aliphatic, and aromatic hydrocarbons such as toluene, n-hexane, butane, and trichloroethylene, as well as nitrous oxide and amyl or butyl nitrite. Especially popular with children is “dusting,” the inhalation of Dust Off, a computer keyboard cleaner that contains d-fluoroethane (279). In the United States nitrous oxide misuse increased steadily during 2000 to 2019 and then rose more sharply during 2020, probably driven by the COVID pandemic (98; 326). Unlike ethanol, overdose of inhalants can cause hallucinations and seizures. Death can result from cardiac arrhythmia, accidents, or aspiration of vomitus. Treatment consists of respiratory and cardiac monitoring. Symptoms usually clear within a few hours. Withdrawal symptoms other than craving are unlikely.

Table 5. Inhalants

Products	Contents
Aerosols	Fluorinated hydrocarbons, propane, isobutane
Cleaning fluids, spot removers, furniture polish	Chlorinated hydrocarbons, naphtha
Glues, cements	Toluene, acetone, benzene, aliphatic acetates, n-hexane, trichloroethylene, xylene, methyl ethyl ketone
Lighter fluid	Aliphatic and aromatic hydrocarbons
Fire extinguishing agents	Bromochlorodifluoromethane
Natural gas	Methane, ethane, propane, butane
Paints, enamels, paint thinners	Toluene, methylene chloride, aliphatic acetates, benzene
Petroleum	Many aliphatic and aromatic hydrocarbons
Anesthetics (surgical supply, whipped cream dispensers)	Nitrous oxide, diethyl ether, halothane, chloroform, enflurane, trichloroethylene
“Room odorizers”	Amyl, butyl, and isobutyl nitrite

Phencyclidine. Classified as a “dissociative anesthetic,” phencyclidine (PCP, “angel dust”) is usually smoked. A related agent, ketamine, (“Jet,” “Special K”), is also used recreationally and either ingested, injected, or smoked (227). A “designer” drug, methoxetamine, has a much longer duration of action than ketamine (64). Also abused is the similarly acting drug, dextromethorphan, which is present in numerous over-the-counter cough syrups (198; 153).

Low doses of PCP cause either euphoria or dysphoria and a feeling of numbness. Higher doses cause agitation, tachycardia, hypertension, fever, ataxia, paranoid or catatonic psychosis, myoclonus, seizures, rhabdomyolysis, coma, respiratory depression, and death. Treatment includes benzodiazepines, forced diuresis, cooling, antihypertensives, anticonvulsants, and cardiorespiratory support. Withdrawal signs are mild, with tremor and nervousness, but craving occurs.

Like PCP, methoxetamine, and dextromethorphan, ketamine is an antagonist at glutamate NMDA receptors. Ketamine’s antidepressant efficacy, however, appears to have a different mechanism, not yet well-understood and remarkable for its rapid onset. Whereas tricyclic antidepressants and monoamine reuptake inhibitors take weeks to achieve symptomatic relief, ketamine’s antidepressant effects are evident within a few hours and can last over a week after a single injection (75).

Anticholinergics. The plant Datura stramonium contains atropine and scopolamine, and recreational ingestion is popular among adolescents. Intoxication produces dry mouth, decreased sweating, fever, tachycardia, and dilated unreactive pupils; overdose can progress to delirium, myoclonus, seizures, coma, and death. Treatment includes physostigmine 0.5 to 3 mg repeated as needed every 30 minutes to 2 hours, plus gastric lavage, cooling, cardiac and respiratory monitoring, and, if necessary, anticonvulsants. Neuroleptics, which have anticholinergic properties, are contraindicated. Withdrawal symptoms do not occur.

Neurologic complications of illicit agents

Trauma. Trauma, including that to the brain, spinal cord, and peripheral nerves, is common among drug abusers. It may be a consequence of the drug’s acute effects--eg, violent behavior during psychostimulant- or PCP-induced psychosis or accidents during marijuana, inhalant, sedative, anticholinergic, or LSD intoxication. Between 1999 and 2010 the prevalence of cannabinoid detection in automobile fatalities increased from 4.2% to 12.2% (33). Much trauma relates to the illegality of particular agents, involving either violent crimes committed to obtain drugs or violence intrinsic to the business methods of drug traffickers. The possibility of serious head or spinal injury must always be considered in patients brought to an emergency room for drug intoxication.

Infection. Parenteral drug users are at risk for local and systemic infections, which can affect the nervous system. Hepatitis leads to encephalopathy or hemorrhagic stroke. Cellulitis and pyogenic myositis can spread to vertebral osteomyelitis, causing radiculopathy or myelopathy. CNS complications of bacterial or fungal endocarditis include brain infarction, brain abscess, meningitis, and rupture of septic (“mycotic”) aneurysm. Tetanus, especially affecting heroin users who inject subcutaneously (“skin-popping”), tends to be severe. Botulism can occur at injection sites or, in cocaine-sniffers, in the paranasal sinuses. Anthrax can also occur at injection sites (138). Malaria has occurred in heroin users from endemic areas.

During 2017, of 38,739 cases of HIV infection reported to the U.S Centers for Disease Control and Prevention, 6.0% were parenteral drug users (53). Among women, HIV most often followed parenteral drug use or heterosexual contact with a drug user. Reflecting on the prescription opioid epidemic, during 2014 to 2015, a single strain of HIV infection was diagnosed in 181 patients from a small community in Indiana; using shared syringes, most had injected an extended-release formulation of the prescription opioid oxymorphone (241). Among nonparenteral drug users, psychostimulants carry risk for AIDS because of risky behavior or, among women, trading sex for drugs (78).

Drug users develop the same neurologic complications of AIDS as other groups and are particularly susceptible to syphilis and tuberculosis. Heroin and cocaine users are often immune suppressed (as are heavy drinkers), and they are at risk for unusual bacterial and fungal infections independent of HIV. Fulminant encephalopathy, most often fatal, affected HIV-infected users of cocaine with or without heroin; autopsy revealed overwhelming microglia activation in the basal ganglia, and the disorder was attributed to synergistic effect of the drugs with HIV proteins (220).

HTLV-I- and HTLV-II-associated myelopathy has been described in parenteral drug users.

Seizures. Seizures may be an indirect consequence of drug use (eg, trauma, CNS infection, stroke) or may occur as a direct result of intoxication or withdrawal. Seizures are commonly encountered during withdrawal from sedatives--barbiturates more so than benzodiazepines. With methaqualone (no longer available in the United States) and glutethimide, seizures can occur during intoxication. In animal models, opioid mu-agonists lower seizure threshold, but seizures during heroin overdose are far more likely the result of additional drug intoxication (eg, cocaine) or drug withdrawal (eg, ethanol). More epileptogenic is meperidine, a consequence of the active metabolite normeperidine. Seizures are also described in tramadol users (16). In a European data-set survey, fentanyl intoxication was much more likely to be associated with seizures than heroin intoxication, and the presence of seizures was associated with worse outcome (329).

Seizures frequently occur during psychostimulant intoxication. With methamphetamine and MDMA, other signs--delirium, fever, hypertension--are usually present. With cocaine, seizures can occur without other evidence of overdose, and they may demonstrate “kindling,” a progressively lowered seizure threshold with repeated nonescalating doses of the drug. Pharmacologically active cocaine metabolites probably account for seizures occurring 12 or more hours after drug use.

Anecdotal reports describe seizure frequency either reduced or aggravated by marijuana. Seizures are a well-recognized feature of “Spice” toxicity, however (43; 257; 329; 116). As previously noted, the non-psychoactive cannabinoid compound cannabidiol has anticonvulsant properties.

Seizures occur in up to 20% of patients presenting with piperazine toxicity (250).

Stroke. As with seizures, stroke in drug abusers may be secondary to systemic complications such as endocarditis, cardiomyopathy, trauma, or hepatitis (43). Concomitant heavy ethanol or tobacco use also increases risk. Heroin nephropathy with uremia, hypertension, and bleeding carries risk for hemorrhagic stroke. Ischemic stroke temporally related to heroin use and in the absence of other risk factors might have an immunologic mechanism. Embolism of foreign material to the brain might also occur. Some cases of acute myelopathy in heroin users are probably vascular in origin. Multiple cerebral infarcts occurred in the setting of heroin-induced hypereosinophilic syndrome (28). Intraparenchymal hemorrhage has also followed heroin use (175).

Intracerebral hemorrhage in methamphetamine and MDMA users can occur in a setting resembling heat stroke, especially at “rave” parties. Methamphetamine was also implicated in cases of systemic and CNS vasculitis resembling polyarteritis nodosa. Small vessel vasculitis causing ischemic and hemorrhagic stroke was also described in amphetamine and methamphetamine users, although many of such reported cases were based on nonspecific angiographic vessel “beading.” Whereas the annual risk of intracranial saccular aneurysm rupture is less than 1% for aneurysms smaller than 7 mm, the risk of smaller aneurysms is significantly higher in methamphetamine users (223).

Over 600 cases have been reported of stroke in cocaine users, roughly half hemorrhagic and half ischemic (284; 43). Most hemorrhagic strokes are probably the result of acute surges of hypertension; in many, imaging has revealed underlying saccular aneurysm or vascular malformation. Most ischemic strokes are probably secondary to cocaine’s direct vasoconstrictive actions on cerebral vessels; vasculitis has rarely been found. Cocaine’s effects on platelets and other coagulation factors probably contribute to stroke risk, and pharmacologically active metabolites probably account for strokes occurring hours or even days after use (278).

Diet pills and decongestants containing phenylpropanolamine were linked with stroke in numerous reports; as a result, the U.S. Food and Drug Administration banned these products. Similar association led to a ban on “dietary supplements” containing ephedra (“ma huang”).

LSD and PCP are vasoconstrictive, and ischemic and hemorrhagic strokes have followed use.

Anecdotal reports describe young people without other risk factors whose strokes occurred during or shortly after smoking marijuana (144; 126; 145; 330; 331). A population-based study of hospitalized patients reported an adjusted odds ratio of 1.76 for marijuana exposure associated with ischemic stroke (324). Another crossover study, after adjusting for confounders such as tobacco, found that heavy marijuana use was associated with a 3-fold increased risk of stroke or transient ischemic attack (136). A case-control study of young adults with ischemic stroke or transient ischemic attack found an odds ratio of 2.3 for marijuana use, but nearly all the patients also smoked tobacco (20). An Australian population survey, adjusting for covariates, found that subjects who used marijuana at least weekly had 4.7 times the rate of stroke compared to nonusers (136).

Proposed mechanisms for stroke in marijuana users include postural hypotension with impaired autoregulation, cardioembolism, and reversible cerebral vasoconstriction syndrome (332). “Multifocal intracranial stenosis” associated with marijuana use was reported in 10 of 48 consecutive young people with acute ischemic stroke (332).

A number of reports describe ischemic stroke in synthetic cannabinoid users (42; 101; 24; 294; 261; 232). A review of 98 cases of cannabinoid-related stroke identified 85 following marijuana use and 13 following synthetic cannabinoid use. Mean age was 32 years. Two-thirds also smoked tobacco. Eighty-seven percent of strokes were ischemic and 8% were hemorrhagic. Half had a favorable outcome, but 5 patients died (331). Ischemic stroke in a young synthetic cannabis user was attributed to cannabinoid-related cardiomyopathy and cardioembolism (163).

Altered mentation. Dementia in drug users may be the result of head trauma, stroke, malnutrition, infection (including HIV encephalopathy), or concomitant ethanol abuse. Whether particular drugs cause lasting cognitive or behavioral change as a direct neurotoxic effect is more difficult to determine. In addition to the above confounders, predrug mental status is usually uncertain, and some drug users are probably self-medicating preexisting psychiatric conditions (eg, psychostimulants for depression) (55; 259).

For these reasons, chronic mental abnormalities described in heroin uses are open to interpretation. A meta-analysis of studies addressing “neuropsychological consequences of chronic opioid use” (including analgesia for intractable pain and methadone replacement therapy) identified significant impairments in verbal working memory and verbal fluency as well as “cognitive impulsivity,” but the authors stressed methodological problems in the studies reviewed (17). Structural and functional imaging demonstrated reduced cerebral grey matter density and decreased white matter fractional anisotropy in heroin users (319; 333). Also described are abnormal connectivity patterns in both heroin users (187) and recreational users of prescription drugs such as oxycodone and hydrocodone (304).

Neuropsychological studies, functional and structural imaging, and animal studies each provide evidence that marijuana causes lasting cognitive impairment (69; 21; 122; 22; 27; 112; 247; 288; 311; 313; 127; 37; 59; 290). In a cohort study that followed 1037 New Zealanders from age 13 years (before any used cannabis) to age 37 years, early and persistent cannabis users showed an average decline in IQ of 8 points compared with nonusers; the difference persisted after adjusting for recent cannabis use or for use of alcohol, tobacco, or other drugs (211). A metaanalysis of 7 cohort studies that included pre- and post-exposure measures of IQ found an average decline of 2 IQ points following exposure to cannabis in youth (246).

Given their greater potency, it is not surprising that cognitive impairment is described in users of synthetic cannabinoids (58; 74; 59; 188).

Neuroimaging studies in cannabis users describe reduced cortical and hippocampal grey matter volume, perhaps reflecting reported abnormalities in time estimation, attention, working memory, cognitive flexibility, decision making, and psychomotor speed (15; 203; 190; 76; 68; 81; 70; 260; 96; 258; 191; 230; 320). Diffusion-weighted MRI and connectivity mapping demonstrate microstructural alterations affecting axonal pathways in long-term marijuana users (336). Children and adolescents are especially vulnerable (41). In a human twin study, decreased amygdala volume in marijuana users was likely the result of genetic or environmental factors, whereas reduced ventral striatal volume seemed more causally related to heavy marijuana use (233). Adolescents with cannabis use disorder showed attenuated loss of thickness in cortical association areas (ie, impaired synaptic pruning) (86). On the other hand, marijuana-using male adolescents at genetic risk for schizophrenia showed abnormally reduced cortical thickness compared to nonusers (102).

In a voxel-based morphometry study of 46 14-year-olds with only 1 or 2 instances of cannabis use, bilaterally greater gray matter volume in inferior medial temporal lobes, posterior cingulate, lingual gyri, and cerebellum was present compared to carefully matched THC-naïve controls. Longitudinal data made it unlikely that gray matter volume differences preceded cannabis use. The regions affected are major components of the brain’s endocannabinoid system (228).

Relevant to the issue of “medical marijuana,” patients with multiple sclerosis who smoke cannabis have greater cognitive impairment than those not using the drug (239).

Several epidemiological longitudinal studies offer evidence that heavy cannabis use is a significant risk factor for developing schizophrenia (95; 183; 271; 201; 248). Such studies show that cannabis use precedes psychotic symptoms, arguing against self-medication or reverse causality (310). Heavy marijuana users are also at increased risk for schizo-affective and other nonaffective psychoses. Reports on depression are conflicting (202; 137).

Although synthetic cannabinoids cause acute psychosis, epidemiological studies such as those implicating cannabis as a risk factor for developing schizophrenia are lacking for synthetic cannabinoids (77).

Controversial is whether psychostimulants predispose to depression or if PCP predisposes to schizophrenia. Dextroamphetamine damages dopaminergic nerve terminals; MDMA damages serotonergic nerve terminals; and methamphetamine damages both dopaminergic and serotonergic nerve terminals. The degree to which the damage is reversible is uncertain, as is its correlation with cognitive dysfunction, which is well documented in heavy users of these agents (39; 217; 125; 182; 26). Methamphetamine neurotoxicity appears to correlate with oxidative stress, excitotoxicity, and neuroinflammation, causing structural and physiological changes in several brain regions of animals and humans and impaired learning (243; 335; 312).

Cocaine does not inflict such damage on nerve terminals, but lasting cognitive impairment and structural alterations in frontostriatal brain systems are described in heavy users (87; 193; 295). Cocaine-treated rats demonstrate abnormal dendritic spines on neurons in the nucleus accumbens, and in both rodents and humans, diffusion tensor imaging shows abnormal fractional anisotropy in cerebral white matter (274; 219). Heavy cocaine users have reduced grey matter volume in prefrontal cortex (88; 143). Monkeys repeatedly self-administering cocaine developed abnormal striatal myelin composition (282). Monkeys receiving modest but chronic doses of cocaine had altered cerebral gray matter densities, which correlated with impaired cognition and persisted after prolonged abstinence (150).

High doses of cocaine decrease hippocampal neurogenesis and impair working memory in rats (291). Rats self-administering cocaine had increased excitatory and decreased inhibitory neurotransmission in the hippocampus, which persisted with abstinence (159). Functional and diffusion tensor imaging studies reveal abnormalities in functional and structural connectivity especially involving frontostriatal circuits in cocaine-dependent humans compared to controls (141; 195; 196). Similar observations were reported in animals (195).

In a study of humans, reduced volume of medial frontal grey matter was related to the number of substances used (cocaine, alcohol, tobacco) rather than to a particular substance; in contrast, ventrolateral frontal grey matter reduction was specifically associated with cocaine use (155).

A review of studies describing the long-term effects of cocaine on cognitive function from 1999 to 2016 concluded, “The current evidence does not support the view that chronic cocaine use is associated with broad cognitive deficits” (100). Another review of placebo-controlled and case-control studies during the same period concluded, “Long-term effects of cocaine show an array of detrimental cognitive functions” (286).

A group of volunteers who had never used MDMA, but were likely to do so in the future, underwent neuropsychological testing and neuroimaging studies, which were repeated after 12 to 36 months. Those who had used MDMA during that interval, even in small doses, demonstrated decreased verbal memory and abnormal fractional anisotropy, and apparent diffusion coefficient in the thalamus, globus pallidus, and cerebral white matter (80). Serotonin transporter binding was decreased in the cerebral cortex of abstinent MDMA users who, although “grossly behaviorally normal,” demonstrated abnormalities on tests of attention, memory, and executive function (166).

A meta-analysis of neuroimaging studies in “stimulant-dependent individuals” found consistent reduction of prefrontal cortex gray matter, which was plausibly linked to impaired “self-regulation and self-awareness” (88). Direction of causality, however, remained open to question.

Gray matter abnormalities affecting cerebral cortex, striatum, and insula showed overlap between cocaine and methamphetamine users, but also significant regional differences in users of one or the other drug (127).

Toluene sniffers are at risk for cerebral white matter lesions and dementia. Lead encephalopathy is described in gasoline sniffers.

Fetal effects. Confounders to determining the effects of illicit drugs on intrauterine development and later cognition include ethanol or tobacco exposure, malnutrition, inadequate prenatal care, and home environment. Infants exposed in utero to heroin are reportedly small for gestational age, at risk for respiratory distress, and cognitively impaired later in life. Therapeutic opioid use during the first trimester is significantly associated with cardiac anomalies and spina bifida (36).

Studies of cocaine’s fetal effects are conflicting. Despite early alarm over an epidemic of “crack babies,” the detrimental effect of in utero cocaine exposure on cognition, although real, appears to be small (179). Neuropsychological testing reveals subtle abnormalities in executive functioning, and diffusion tensor imaging shows frontal white matter abnormalities (262; 18; 180; 184). A 10-year prospective study controlling for such confounders as additional drugs and environmental influences found that first trimester exposure to cocaine carried risk for reduced height, weight, and head circumference and for lower sociability and increased withdrawn behavior (254). Compared to controls, adolescents exposed prenatally to cocaine had significantly thinner right dorsolateral prefrontal cortex (186).

A meta-analysis of studies of newborns exposed in utero to cocaine found “clear evidence that crack cocaine contributes to adverse prenatal outcome,” including preterm delivery, placental displacement, reduced head circumference, small for gestational age, and low birth weight (83). A review of “congenital cocaine syndrome” concluded that “maternal cocaine use during pregnancy…is associated with a host of neurological and developmental abnormalities in the offspring,” including microcephaly, perinatal cerebral infarction, limb and genitourinary malformations, cognitive delay, brain abnormalities on MR diffusion tensor imaging, lower volumes of cortical grey matter, and later propensity to abuse tobacco, alcohol, or marijuana (298). Proposed mechanisms for fetal damage include compromised placental and cerebral blood flow and toxic interaction with monoaminergic synapses.

Prenatal exposure to methamphetamine is significantly associated with restricted fetal growth; depressed arousal in neonates; lower verbal memory, spatial memory, working memory, attention, and visual-motor integration in older children; and lasting metabolic and structural changes, especially involving frontostriatal circuitry (297; 264).

The endocannabinoid system is critically important in embryological development, including angiogenesis, cellular replication, and tissue differentiation (104; 03). In utero marijuana exposure is associated with decreased birth weight and length and with a variety of cognitive and behavioral abnormalities, especially impaired executive function (48; 154; 135; 149; 97; 255). Prenatal exposure disrupts cytoskeletal dynamics necessary for the establishment of axonal connectivity (301). In mice, prenatal exposure to a synthetic cannabinoid resulted in major malformations including face, eyes, and brain (cortical dysplasia, exencephaly, and holoprosencephaly) (111). Collectively, animal and human studies provide evidence that although cannabis is not teratogenic in the sense of causing morphological abnormalities, it does have negative long-term effects on executive function (attention, inhibitory control, planning) (120).

In utero solvent exposure, especially toluene, is teratogenic in both animals and humans.

Miscellaneous effects. Severe sensorimotor polyneuropathy occurs in sniffers of glue containing n-hexane. Quadriplegia develops over a few weeks, and recovery is usually incomplete. Residual spasticity implicates additional CNS damage.

A number of reports have described sensorimotor polyneuropathy and brachial or lumbosacral plexopathy in heroin users (71). If drug-related, the mechanism is presumably immunologic, perhaps related to an adulterant.

Rhabdomyolysis with myoglobinuria and renal failure has followed use of heroin, methamphetamine, cocaine, and PCP (as well as ethanol). With cocaine, rhabdomyolysis can be a feature of overdose or occur without other evidence of toxicity. Treatment includes forced diuresis and urinary alkalinization.

Nitrous oxide sniffers develop myeloneuropathy clinically and pathologically indistinguishable from cobalamin deficiency. Anemia is absent, and serum vitamin B12 levels are usually normal. The disorder is caused by inactivation of the cobalamin-dependent enzyme methionine synthase.

Severe, irreversible parkinsonism developed in Californians injecting a street analog of meperidine contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a metabolite of which is toxic to neurons in the substantia nigra. Symptoms responded to levodopa, but typical side effects including dyskinesias were prominent, and attempts to wean off dopaminergic therapy were unsuccessful.

“Chasing the dragon” refers to heating heroin on metal foil and inhaling the vapor through a straw or tube. A devastating spongiform leukoencephalopathy occurs in heroin users practicing this technique. Apathy and ataxia rapidly progress to varying combinations of dystonia, spastic quadriparesis, blindness, myoclonus, pseudobulbar palsy, and, in some cases, death. Neither the responsible toxin nor the pathophysiological mechanism has been identified (65; 02). A similar spongiform encephalopathy has infrequently been reported after intravenous heroin (242). Case reports also describe refractory hydrocephalus in dragon chasers (45; 73). Rarely, similar demyelinating and vascular lesions have been described in cocaine users (25). A single case report describes similar leukoencephalopathy in a synthetic cannabinoid user (06).

Chronic cocaine users often develop chorea or dystonia temporally associated with use and sometimes lasting days or weeks into abstinence. Cocaine exacerbates symptoms of Tourette syndrome, and tics have appeared in previously asymptomatic users (40).

Clinical and population studies have shown that methamphetamine users are up to 3 times more likely to develop Parkinson disease or parkinsonism, and median age of Parkinson disease onset is 6 years earlier in methamphetamine users compared to nondrug users with Parkinson disease. Risk for Parkinson disease is not shared by users of cocaine or MDMA (182; 26).

Acute sensorineural hearing loss, often permanent, has been associated with a number of opioids, including prescription use and heroin. A proposed mechanism is cochlear ischemia (197).

Leukoencephalopathy can affect the cerebellum in toluene sniffers, producing prominent ataxia.

Cannabinoid hyperemesis syndrome has become more prevalent with increasing use of cannabis, increasing concentration of delta-9-THC in marijuana products, and increasing use of more potent synthetic cannabinoids (285; 252). In heavy chronic users, protracted severe vomiting follows drug use, lasts 1 to 2 days, recurs with further use, and disappears with abstinence (293). Pathophysiological mechanism is unclear, as is the often dramatic relief of symptoms with hot showers and baths and topical application of capsaicin.

Marijuana inhibits luteinizing and follicle-stimulating hormones, causing reversible impotence and sterility in men and menstrual irregularity in women.

In 2019, an outbreak of severe pulmonary disease affected users of electronic cigarettes and vaping products. The disorder was traced to products containing delta-9-THC plus vitamin E acetate. As of 2020, 68 deaths and over 2800 hospitalizations had been reported (293).

Ephedrone (methcathinone) manufacture involves potassium permanganate oxidation of ephedrine or pseudoephedrine. Intravenous use is associated with an irreversible parkinsonian-like extrapyramidal syndrome attributed to manganese toxicity (289).

In a case-controlled study, MDMA was an independent risk factor for sleep apnea in abstinent users (208). The mechanism is probably related to MDMA neurotoxicity affecting CNS serotonergic axons. Whether sleep apnea contributes to the cognitive impairments observed in MDMA users is unclear.

Hallucinogen users not only experience flashbacks, but the visual phenomena—geometric shapes, objects in the peripheral field, flashes of color, enhanced color intensity, trailing and stroboscopic perception of moving objects, after images, halos, and macro/micropsia—can persist for years (“hallucinogen-persisting perception disorder”) (229).

Since 2003, U.S. cocaine samples have frequently been adulterated with the immunomodulatory drug levamisole, which is currently present in up to 70% of cocaine samples in the world. A psychoactive metabolite of levamisole, aminorex, has psychostimulant properties and therefore might increase or prolong a cocaine high. Complications attributable to levamisole in cocaine users include leukopenia, cutaneous vasculitis with perinuclear antineutrophil cytoplasmic antibodies (pANCAs), and an irreversible demyelinating leukoencephalopathy (38; 317).

The endocannabinoid anandamide is metabolized by fatty acid amide hydrolase (FAAH). Inhibitors of FAAH raise endocannabinoid levels, and in animal models, treatment with such inhibitors has shown analgesic efficacy. In a phase 1 trial in humans, several subjects developed severe acute leukoencephalopathy, 1 case progressing to brain death (160).

“Saturday night retinopathy” refers to visual loss following drug or alcohol intoxication with prolonged direct compression of the orbit. In 1 reported case, there was also bilateral hippocampal ischemia and amnesia (44).

For unclear reasons the anti-vitamin K anticoagulant bradifacoum, present in rodenticides, has become a common adulterant in preparations of synthetic cannabinoids. Outbreaks of coagulopathy, including spontaneous intracranial hemorrhage with fatal outcome, have been reported (32).

Illicit drugs carry an enormous variety of other adulterants, often pharmacologically active. Reports describe acetaminophen, aminopyrine, diltiazem, diphenhydramine, phenacetin, and quetiapine. Complications include anemia, bone marrow damage, cancer, cardiac arrhythmia, hemolytic uremic syndrome, neutropenia, and renal failure (277).