Hallucinogen Toxicity 

Updated: Aug 15, 2018
Author: Joseph L D'Orazio, MD, FAAEM; Chief Editor: Sage W Wiener, MD 

Overview

Practice Essentials

Hallucinogens comprise a unique collection of substances that are used to induce hallucinations or alterations of consciousness. Hallucinogens are drugs that cause alteration of visual, auditory, or tactile perceptions but are also referred to classes of drugs that cause alteration of thought and emotion.

Naturally occurring hallucinogenic substances have been used worldwide for millennia to induce altered states for religious and spiritual purposes. While these practices still exist, the use of synthetic hallucinogens for recreational purposes is much more common today.

Patients under the influence of hallucinogens may exhibit a wide range of behaviors with the potential to rapidly fluctuate from a relaxed, euphoric state to one of extreme agitation and aggression. They should be placed in a calm and relaxed environment. Security personnel, physical restraints, and sedating agents should be prepared and readily available if agitation suddenly develops.

Physical restraints should be used as a bridge to sedation. Benzodiazepines are the first-line agents, and should be administered liberally.

All patients should be evaluated for the presence of emergent medical conditions, including traumatic injuries and cardiac arrhythmias. Special attention should be paid to the patient’s temperature, as many hallucinogenic agents can induce hyperthermia.

Background

Hallucinogens can be classified and grouped by chemical structure and the compound from which they are derived. Chemically related substances tend to exhibit similar effects. Many other agents can be classified as pseudohallucinogens because they produce psychotic and delirious effects without the classic visual disturbances of true hallucinogens.

There is no perfect method to categorize hallucinogenic substances because many overlap in structure, pharmacology, and clinical features. One system groups hallucinogens into the following families[1] :

  • Indole alkaloids (tryptamines)
  • Piperidines/piperazines
  • Phenylethylamine derivatives
  • Miscellaneous psychoactive substances

Some common indole alkaloids (tryptamines) include dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin. The most common piperidines and piperazine are phencyclidine (PCP), ketamine, benzylpiperazine (BZP), and 3-trifluoromethylphenylpiperazine (TFMPP). The phenylethylamine derivatives are the broadest hallucinogen group and incorporate many substances. While 3,4-methylenedioxy-N -methylamphetamine (MDMA; ecstasy, Molly) is likely the most common of the phenylethylamine derivatives, some others include such newer novel synthetics as cathinones (“bath salts”), the 2C family of drugs, as well as their N-o-methoxybenzyl analogs (NBOMe).

A number of naturally occurring hallucinogens can be found in plants and mushrooms and grow in many locations in the United States. Many of these substances have long been used in ritualistic medicine, and some are emerging agents of recreational use. Included in these naturally occurring substances are DMT, psilocybin and psilocin, mescaline, salvinorin A, lysergic acid amide (LSA), and atropine and scopolamine.

Ayahuasca

DMT is a naturally occurring tryptamine found in over 65 species of plants, primarily in the South American region. For centuries, DMT-containing plants have been used for religious purposes, as they rapidly induce brief but powerful hallucinogenic effects. DMT is primarily smoked or insufflated, because it is orally inert due to rapid inactivation by intestinal monoamine oxidase (MAO). This inactivation can be overcome by the addition of a monoamine oxidase inhibitor (MAO-I), as is found in the ritualistic brew Ayahuasca.

Over the past decade, DMT use has gained popularity following the publication of the 2001 book DMT: The Spirit Molecule by Dr. Rick Strassman, MD. Of note, DMT ingestion produces significant gastrointestinal distress and universal emesis shortly after ingestion, the development of which is a desired effect in spiritual purgative ritual use.

Bath Salts

"Bath salt" is the informal street name given to designer drugs containing substituted or synthetic cathinone chemicals. These substances are sold in plain sight surreptitiously as innocuous products such as "baths salts" and are marketed under names such as "Bliss," "Ivory Wave," and "Vanilla Sky." "Not For Human Consumption" labels are utilized in an effort to circumvent regulation.

Synthetic cathinone or "bath salt" use has emerged over the last decade and gained popularity in large part due to these agents' accessibility and ambiguous legal status. In 2011, the Drug Enforcement Administration (DEA) designated methylenedioxypyrovalerone (MDPV), methylone, and mephedrone as Schedule I substances, to make their sale and possession illegal. However, the clandestine production of these substances remains ahead of legislative action to avoid prohibition. Since then, additional cannbinoids have been scheduled by the DEA, but it can be difficult for the DEA to keep up with products that contain an evolving variety of cannabinoids.

Cathinones are generally amphetamine-like in structure. Some, with a methylene-dioxy- group—such as methylone and 3,4-methylenedioxypyrovalerone (MDPV)—are MDMA-like and can be considered hallucinogens. Others—such as cathinone, metcathinone, and mephedrone—have clinical effects more akin to amphetamine and methamphetamine

Cathinones are found in the leaves and stems of Catha edulis (khat), a plant native to East Africa and the Arabian Peninsula. Historically, consumption of this naturally occurring cathinione has been through chewing the fresh, unprocessed leaves of the khat plant. Substituted cathinones found in "bath salts" are created in clandestine labs and have effects similar to those of amphetamines and the phenethylamine class.

Use of the cathinones has stemmed from the custom of khat chewing in indigenous areas, which dates back thousands of years and remains culturally acceptable in these regions.[2] Currently, substituted cathinones such as MDPV, methylone, or mephedrone are sold in the form of crystalline powders, which are taken by insufflation.

Cannabinoids and Synthetic Cannabinoids

Cannabis sativa is the scientific name for the plant commonly known as marijuana. It is used recreationally and medicinally for many conditions. The Cannabis sativa plant contains high levels of tetrahydrocannabinol (THC) and other psychoactive cannabinoids. Although THC is the principal psychoactive component of cannabis, this plant is chemically complex and contains many other cannabinoids, including cannabidiols, cannabinol, and tetrahydrocannabivarin (THCV). The psychoactive effects seen with cannabis use include relaxation, euphoria, and heightened mood.

Synthetic cannabinoids act as cannabinoid receptor agonists. Many were initially developed as research chemicals designed for studying cannabinoid receptors, and were only later diverted as recreational drugs. These synthetic cannabinoids are added to herbal mixtures to give them the appearance of marijuana and to facilitate smoking to produce what many term a "legal high" or "herbal high."

These products, much like the bath salts, are sold surreptitiously as "herbal incense" and are commonly referred to as "spice" or "K2". The label "Not For Human Consumption" is used to avoid regulation.

In 2011, five synthetic cannabinoids [JWH-018, JWH-073, CP-47,497, JWH-200, and cannabicyclohexanol (CCH)] were designated Schedule I by the Controlled Substances Act, which made it illegal to manufacture, import, possess, distribute, or use these substances. Since then, additional cannbinoids have been scheduled by the DEA, but it can be difficult for the DEA to keep up with products that contain an evolving variety of cannabinoids.

Some synthetic cannabinoids users use these substances to elude detection on standardized drug testing. While THC from marijuana use is easily detected on a standard urine drug test, most synthetic cannabinoids are not similar in structure to THC and therefore do not trigger positive results on typical urine drug screens. This has led to its popularity in populations with obligatory drug testing (eg, the penal system, psychiatric setting, military, department of transportation, professional athletics). Others use synthetic cannabinoids because they are inexpensive and readily available, which has made these drugs popular among the homeless population in some cities.

Antimuscarinic xenobiotics

Atropine and scopolamine are found in a variety of plants, and overdoses can induce hallucinations as well as a variety of more serious effects. Both are found in Datura stramonium (Jimson weed), Atropa belladonna (deadly nightshade), and Mandragora officinarum (mandrake). Scopolamine alone occurs in Hyoscyamus niger (henbane).

Dextromethorphan

Dextromethorphan (DXM) is an antitussive agent found in many over-the-counter cough and cold medicines. DXM’s clinical effects at doses higher than recommended include a euphoric-like effect, alteration of perception, and visual hallucinations. When used recreationally in high doses, DXM acts like ketamine or PCP, blocking NMDA receptors and causing an altered level of consciousness commonly described as a dissociative state. Clinical effects vary by dose and time; users commonly refer to these stages as "plateaus."[3]

The over-the-counter remedies that contain DXM also typically contain other ingredients, such as decongestants, antihistamines, analgesics, and expectorants. Users who take these products for the DXM may unwittingly consume toxic amounts of those other ingredients.

Ecstasy

This designer hallucinogenic drug is widely used recreationally as a "club drug" and is found at night clubs, festivals, raves, and concerts. While the names "ecstasy" and "Molly" originally referred to MDMA, many drugs are sold by those names today, and MDMA is known by other street terms as well, such as "E" and "X".[4]

MDMA produces hallucinogenic effects by causing release of serotonin, norepinephrine, and dopamine. Clinical effects of this drug are similar to those of other phenethylamine drugs, but the methylene-dioxy ring makes it more serotonergic than amphetamines that lack this structure. 

LSD and LSA

LSD was first synthesized in 1938 by Albert Hoffman in an attempt to derive new analeptic agents from extracts of the ergot fungus Claviceps purpurea. It first appeared in the United States in 1949 when it was used as a model to study schizophrenia due to its potent psychotomimetic effects. The applications of LSD quickly broadened to include numerous other medical and clandestine uses, including interrogation and mind-control experiments.

LSD use also was believed to enhance creativity and promote well-being. By the late 1950s, use of LSD had been proposed as a way to achieve intellectual and spiritual awakening and enlightenment. Initial studies in the early 1960s concluded that the drug was safe. By the mid 1960s, however, reports of increasing illicit use and adverse effects in patients treated with LSD led the federal government to begin regulation and restriction of its use.

Overall hallucinogen use is estimated to have remained fairly constant rover the past decade. While LSD is included in national drug trending reports, the accuracy of these for actual LSD use is complicated by novel non-lysergamide hallucinogenic compounds being marketed as LSD.

Naturally occurring lysergamides can be easily found in the morning glory species (Ipomoea violacea and Rivera corymbosa) and Hawaiian baby woodrose (Argyreia nervosa), the seeds of which contain these hallucinogenic alkaloids. Both plants and seeds are legal to purchase in the United States for landscaping or decorative purposes, but extraction of the active lysergamide is illegal, because LSA is a Schedule III controlled substance.

Mescaline

Mescaline is a phenylethylamine-derived alkaloid that is found worldwide in a variety of cacti, the best known being the North American peyote cactus. Similar to the mushroom-derived hallucinogens, mescaline in the form of peyote cactus buttons has been used in rituals by many Native Americans for centuries. To achieve the desired effect, 5-10 buttons are chewed and ingested.

NBOMe

This new class of designer research chemicals includes highly potent hallucinogenic serotonin agonists. 25I-NBOMe and 25C-NBOMe are the two most common forms of this drug. "Bomb" or "N-Bomb" is commonly sold on blotter paper, which the user places against the buccal mucosa or under the tongue, just like LSD. NBOMe is commonly misrepresented as LSD because of their similar routes of administration and effects. While the two drugs are similar, there are numerous reports of fatal overdoses in the US due to NBOMe.[5, 6]

Nutmeg

Nutmeg (seed of the Myristica fragrans tree) is widely available for culinary use. Historically, nutmeg has been used as an abortifacient and to induce menses, albeit ineffectively. In large quantities, nutmeg can produce anticholinergic effects, including visual hallucinations due to activity of the compound myristicin. While often ingested intentionally for hallucinogenic effects, case reports exist where therapeutic misadventures for naturalistic purposes have induced hallucinations.[7]

Phencyclidine and ketamine

PCP and ketamine are piperidine derivatives with potent anesthetic and illusionogenic properties. PCP was developed at Parke-Davis and Company in the late 1950s as a potent and effective dissociative anesthetic. Its use was short-lived, as it produced strong adverse side effects, including emergence reactions with extreme agitation, disorientation, and hallucinations.[8] PCP enjoyed a short use in the veterinary world during the 1960s, during which time it was diverted in pill form throughout the San Francisco region and eventually spread to surrounding states in the form of powder ("angel dust") added to plant substances for smoking.

PCP use has declined nationally over the past three decades, but remains common in certain cities including Philadelphia and Washington, D.C. PCP is most commonly sold as a liquid solvent in which the user will dip a cigarette or marijuana joint (a so-called wet, dip, dipper, or sherm)and the product is smoked, producing rapid clinical effects.[8] Because of PCP’s strong volatile solvent smell, it often been referred to as "embalming fluid" or "formaldehyde." This had led to some users to erroneously believe that the clinical effects from abusing formaldehyde are similar. Currently, illicit PCP is not diverted from health-care sources, but rather produced illegally in clandestine labs due to ease of synthesis and readily available precursors.[9]

Ketamine was synthesized in 1962 as a replacement for PCP, and it remains a widely used anesthetic with increasing non-operative usage, including in emergency departments and the pre-hospital setting.[10, 11]  More recently, ketamine in subanesthetic doses has been studied for use as an antidepressant, particularly in cases that are refractory to standard treatment or accompanied by suicidality.[12]

Ketamine is used recreationally primarily as an insufflated powder. Its effects are dose-dependent and wide-ranging, from mild alteration of sensorium to complete dissociation of consciousness with powerful and sometimes disturbing hallucinogenic experiences known as the "K hole". Hallucinations from ketamine and PCP are due to agonism at the sigma-receptor (previously classified as an opioid receptor). Ketamine is known for being more psychologically addictive than most psychedelics. It is commonly used at large concerts and clubs.[13]

Psilocin and psilocybin

Psilocin and psilocybin are indole alkaloids that are found worldwide in a variety of mushrooms including the genus Psilocybe and have been used in religious rites for over 6,000 years. Ingesting only a few mushroom caps can produce hallucinogenic affects, but in general large numbers of mushrooms are required.

Psilocybin, the prodrug to psilocin, induces a sense of euphoria, causes visual hallucinations, and can alter spiritual perception (entheogen). The drug was widely studied in the 1960s by Timothy Leary and Richard Alpert in the Harvard Psilocybin Project and has recently gained a renewed interest in its treatment for many disorders including obsessive-compulsive disorder, cluster headaches, drug dependence, and anxiety in advanced-stage cancer.[14, 15]

Salvinorin A

Salvinorin A is a naturally occurring hallucinogen that is found in a variety of plants but is named from Salvia divinorum, or diviner's sage, a member of the mint family.[1] Salvinorin A is unique in that—unlike other known hallucinogenic substances that interact with serotonin (5-HT2 receptors) metabolism, with the sigma receptor, or with muscarinic receptors—it is the first known naturally occurring kappa-opioid receptor agonist.[16] This substance has been used by the Mazatec Indians in Mexico for ceremonial purposes. While Salvia divinorum and salvinorin A are not classified under the Controlled Substances Act, several states have placed regulatory controls on either or both.[17]

Other designer drugs

This group of drugs refers to psychoactive drugs initially discovered in pharmaceutical or research labs but sold illegally by clandestine labs. Just like other hallucinogens, these drugs can be classified by effect or chemical structure. Most of these drugs belong structurally to the phenylethylamine derivative group. The newer designer drug category is the most rapidly growing and changing group of drugs among the hallucinogens. While this is an ever-changing, some of the common substances include the MDMA congeners (eg, MDA, MDEA, MDPV), the 2C family of drugs (eg, NBOMe, 2CB, 2CI, and Bromodragonfly), and the D series of ring-substituted amphetamines (eg, DOB, DOI, DOM).

This category is likely the most dangerous group of drugs, for many reasons. These drugs are typically made in clandestine labs by amateur chemists, which produces variable results with poor quality control. Oftentimes these clandestine labs may inadvertently produce a drug other than their intended product, although it may be structurally similar. This unknown agent may have untoward effects above and beyond those of the intended drug. Dosing and potency are also common problems with clandestine labs — especially when chemicals are added to blotter paper or organic material, as is done with NBOMe and synthetic cannabinoids, respectively.

Pathophysiology

Hallucinogenic substances primarily exert their effect on the central nervous system by way of neurotransmitter level manipulation. Stimulating secretion, inhibiting reuptake, delaying enzymatic breakdown, or directly stimulating or inhibiting neurotransmitter receptors are all mechanisms by which hallucinogens can increase the synaptic concentration of the major neurotransmitters (ie, norepinephrine, serotonin, and dopamine). Small differences in structure affect neurotransmitter levels differently, which leads to the wildly varied clinical effects.

Tryptamines (eg, LSD, psilocybin, DMT) are strong partial agonists at the 5-hydroxytryptamine (5-HT) receptors. MDMA (ecstasy) enhances presynaptic release and reuptake of serotonin and norepinephrine.[18] JWH-018 and other synthetic cannabinoids are cannabinoid receptor (CB1 and CB2) agonists that can exert a secondary effect on the balance of circulating catecholamines.[19]

Although these small differences help to explain the varied hallucinogenic experiences, they can also predict the spectrum of deleterious effects. Serotonin syndrome (serotonin toxicity) can occur with any agent that increases concentrations of serotonin, including LSD, psilocybin, and mescaline.[20] The neurotransmitter dopamine is associated with the reward system of the brain. Substances that stimulate release or inhibit reuptake of dopamine typically exhibit a strong addictiveness, as seen with cathinones (bath salts) and methamphetamines.

Unfortunately, even if structure and mechanism of action are similar, subtle differences in potency can lead to devastatingly different effects, as seen in the psychosis that can occur with the highly potent cannabinoid receptor agonists but that is not routinely associated with marijuana.

Epidemiology

Frequency

United States

The 2016 National Survey on Drug Use and Health (NSDUH) found that in 2016, an estimated 1.4 million people aged 12 or older were current users of hallucinogens, representing 0.5 percent of that population. Current hallucinogen use was highest in young adults aged 18 to 25 years, 668,000 of whom (an estimated 1.9% of that population)  had used hallucinogens in the past month.

The NSDUH's category of hallucinogens includes LSD, phencyclidine (PCP), peyote, mescaline, psilocybin mushrooms, MDMA (ecstasy or Molly), ketamine, DMT/AMT/Foxy, and Salvia divinorum. The NSDUH added ketamine, DMT/AMT/Foxy, and Salvia divinorum to the category in 2015, so 2016 estimates of hallucinogen use are not comparable with estimates prior to 2015.[21]

In 2014, the percentage of adolescents (aged 12 to 17) who were current hallucinogen users was similar to the percentages in 2012 and 2013, but it was lower than the percentages in most years from 2002 through 2011.[22]  

Of hallucinogens on the survey, MDMA appears to be the most popular, with 609,000 users in 2014. The percentage of users over age 12 years in 2014 was similiar in most years from 2002 to 2013. However, among adolescents, current MDMA usage was lower than the percentages in most years from 2002 to 2013.[22]

According to the US Centers for Disease Control and Prevention (CDC), the number of acute poisonings from synthetic cannabinoids rose sharply between 2010 and 2015. Of 456 cases of synthetic cannabinoid intoxication reported to a toxicology case registry during that period, 277 (61%) involved synthetic cannabinoids only. Three deaths were recorded, one with synthetic cannabinoids alone and two with multiple-agent exposures.[23]

In March 2018, the Illinois Department of Public Health reported cases of unexplained bleeding in users of synthetic cannabinoids. Subsequent testing showed that the cannabinoids had been adulterated with brodifacoum, a long-acting vitamin K antagonist anticoagulant that is often used as a rodenticide. By late May 2018, the CDC had received reports of 202 cases: 164 from Illinois, 20 from Maryland, and the remainder from Florida, Indiana, Kentucky, Missouri, Pennsylvania, Virginia, and Wisconsin. Five cases were fatal.[24, 25]

International

Australia reported that in 2014, MDMA was second only to cannabis as the most commonly used illicit drug, with 2.1 million (10.9%) people aged 14 or older having used the drug during their lifetime and 500,000 having done so in the past 12 months, representing 2.5% of the population[26]

In Europe, an estimated 1.8 million young adults (15–34) used MDMA in 2014 (1.4 % of this age group), with national estimates ranging from under 0.1 % to 3.1 %.[27]

Globally, use of MDMA has been declining, according to many reports. However, the United Nations World Drug Report shows that use  in Europe is still increasing. The regions with highest prevalence of MDMA use are Australia and Oceania (2.9%), North America (0.9%) and Europe (0.7%).[28]

Mortality/Morbidity

Deaths from drug overdose are currently the leading cause of injury death in the United States and have been rising steadily over the past two decades.[29] Most of these deaths are due to opioids, and data on mortality directly attributable to hallucinogen use are not readily available.

The Drug Abuse Warning Network (DAWN), a public health surveillance system that monitored drug-related morbidity and mortality, estimated that 49% of all emergency departments visits are due to drug use or misuse.[30]

Race-, Sex-, and Age-related Demographics

According to the 2014 NSDUH, rates of illicit drug use in the past year among different ethnic groups were as follows[22] :

  • American Indians or Alaska Natives: 24.0%
  • Native Hawaiians or other Pacific Islanders: 21.3%
  • Blacks: 19.5%
  • Whites: 16.9%
  • Hispanics: 15.6%
  • Asians: 8.0%
  • Two or more races: 23.3

According to the 2014 NSDUH, the rate of illicit drug use was higher in males, at 19.8%, than in females, at 13.7%. Males were more likely than females to be users of hallucinogens (2.1% vs. 1.1%).[22]

The age group with the highest incidence of hallucinogen use in 2014 was adults 26 year olds and older.  An estimated 0.3 percent of this population were current users of hallucinogens in 2014 which represents 535,000 individuals. Estimates of current hallucinogen use ranged between 0.1 and 0.3 percent from 2002 to 2014, with the 2014 estimate being slightly higher than the estimates in 2003, 2004, 2006, 2008, 2010, and 2011.[22]

 

Presentation

History

Although most patients who present to the emergency department (ED) with hallucinogen intoxication have a history of recent ingestion, not all are diagnosed easily.[10] Some patients may provide a history of consuming a specific drug, but may in fact have used a different one, as surreptitious substitution of one drug for another by the manufacturer is common; the product in question may not even have contained an active hallucinogenic agent at all.

Altering drug composition or dose can have profound consequences on presentation. In addition, these products are often adulterated with drugs such as acetaminophen, caffeine, barbiturates, antipsychotics, or other pharmaceuticals.[4]  In cases of synthetic cannabinoids adulterated with brodifacoum, patients have presented with signs and symptoms of coagulopathy (eg, bruising, nosebleeds, excessively heavy menstrual bleeding, hematemesis, hemoptysis, hematuria, flank pain, abdominal pain, and bleeding gums or mouth).[24]

While a broad differential should be maintained in cases of altered mental status or psychotic behavior, often key historical details may be elicited from family members or bystanders. Experienced users often have contingencies for a “bad trip” and may be accompanied by a designated sitter who can provide information. Without this information, reliance on prehospital personnel to provide a history of empty bottles, containers, or drug paraphernalia is key.

The duration of effect may also provide helpful clues for the agent ingested. DMT has the shortest duration of action, peaking in seconds and lasting less than 60 minutes. MDMA may produce effects for 4-8 hours, whereas LSD can be active for well beyond 12 hours. Novel phenylethylamine derivatives have widely variable durations of action, ranging from 90 minutes to 20 hours or more.[31]

Physical Examination

Patients under the influence of hallucinogenic agents may have a wide range of physical exam findings, depending on the agent.

General features of simple, uncomplicated hallucinogen effect include altered sensorium, tachycardia, tachypnea and possibly mild to moderate blood pressure elevations. Hyperthermia is not a prominent feature of uncomplicated, single-agent hallucinogen use in standard doses and its presence should prompt consideration of polysubstance interaction, including serotonin syndrome or ingestion of an anticholinergic agent such as dextromethorphan or Datura.

Physical exam findings may include marked mydriasis, especially in the setting of tryptamine or lysergamide use, or with anticholinergics. Findings on a focused neurologic examination are often normal except in the setting of phencyclidine or ketamine use, which can produce marked horizontal, vertical, or rotatory nystagmus.

Muscle tremors and fasciculation may be found with the use of phenylethylamines. Frank muscular rigidity, hyperreflexia of the lower extremities, or clonus should prompt the consideration of serotonin syndrome, which may be triggered by DMT/Ayahuasca or dextromethorphan in patients already on a serotonergic antipsychotic. Finally, gastrointestinal distress is common with mescaline, DMT, or Ayahuasca use and is viewed to be a desirable occurrence when used for spiritual purposes.

Special attention should be paid to patients who present with delayed gastrointestinal effects of nausea and vomiting greater than 6 hours after ingestion of hallucinogenic mushrooms. While psilocybin-containing mushrooms are fairly recognizable, other hallucinogenic mushrooms including Amanita muscaria may look similar to the Amanita phalloides mushroom, which is extremely hepatotoxic and may be mistakenly ingested by inexperienced individuals.

Finally, a careful physical exam should be performed to evaluate for traumatic injury, which is not infrequently associated with hallucinogen use. As with all types of illicit substances, patients under the influence of hallucinogens may have abnormal sensory perceptions and abnormal behaviors, resulting in unrecognized injury.

Physical exam findings that are inconsistent with hallucinogen use should prompt appropriate general medical evaluation.

 

DDx

 

Workup

Laboratory Studies

Testing directed at confirming exposure to a hallucinogenic substance is rarely useful. Treatment is symptom guided and results of confirmatory testing are not rapidly available.

The urine drug screen (UDS) may be misleading when used to diagnose the cause of presenting clinical features. The UDS is limited and often does not contain a screen for common hallucinogens. In addition, false-positive and false-negative results are common with the typical UDS immunoassay (eg, diphenhydramine, dextromethorphan, and venlafaxine have been reported to cause a false-positive phencyclidine screen).[32, 33] Finally, even a true-positive UDS result does not always identify the cause of a patient's current presentation; for example, the UDS could be positive for phencyclidine because the patient took it 3 days ago.

Laboratory tests such as basic metabolic profiles, blood gases, hormonal concentrations (thyroid-stimulating hormone, cortisol), and creatine kinase can be used to identify complications from hallucinogens and exclude alternative causes of altered mental status (eg, acid-base disturbances, metabolic and endocrine pathology, electrolyte abnormalities, rhabdomyolysis, renal failure, or stroke).

When exposure confirmation is necessary (ie, forensic cases, research purposes) expanded drug testing can be performed using specialized immunoassays, liquid chromatography and mass spectrometry, or a variety of other methods which are available through specialized reference laboratories.

Imaging Studies

Imaging is rarely useful in evaluating the effects of hallucinogen exposure. However, advanced imaging, including computed tomography or magnetic resonance imaging of the brain, can be useful in identifying complications and clinical disorders often associated with recreational hallucinogen use, including trauma, infection, hyperthermia, and hypertensive crisis.

 

Treatment

Prehospital Care

Prehospital care should focus on preventing harm and transporting patients to an appropriate facility for further evaluation. It is important to note that patients under the influence of hallucinogens may exhibit a wide range of behaviors with the potential to rapidly fluctuate from a relaxed, euphoric state to one of extreme agitation and aggression. Calm, reassuring, and nonthreatening behavior can be useful in "talking down" patients to allow care and interventions to proceed. Often times, transporting a severely agitated patient requires numerous responders.

In the setting of significant agitation, the primary goal for transport is to ensure both patient and provider safety through sedation and physical restraint. Whenever possible, adequate sedation should be the primary objective in behavioral control. Cases of arrest-related deaths (ARD) are not infrequent in the setting of physical restraint.

Various mechanisms have been proposed for sudden cardiac death related to restraint use including the combination of marked lactic acidosis due to struggling against restraint combined with impaired chest wall motion. Patients pinned down by law enforcement may also have marked compression of the inferior vena cava. If physical restraint must be used, it should be performed with the patient in the supine position when possible; the “hogtied” approach should be avoided at all costs due to an increased association with sudden death.[34, 35] Physical restraints should be used as a bridge to allow for appropriate sedation.

The choice of agent for pharmacologic restraint may be dictated by local prehospital protocols. Whenever possible, however, benzodiazepines should be the first-line agent, as they are effective both intravenously (IV) and intramuscularly (IM), have rapid onset of activity, and do not have the potential for cardiac conduction delays or decreased seizure threshold associated with antipsychotics such as haloperidol or droperidol. IM diazepam (Valium) or midazolam (Versed) have rapid onset of action and should be used in preference to lorazepam (Ativan) if safe IV access is not obtainable. Diazepam is also a good choice if IV access is available, but absorption can be unpredictable by the IM route.

IM ketamine (4-5 mg/kg IM) may be a promising approach for the pre-hospital management of agitated delirium.[36, 37] When used intramuscularly, ketamine has a rapid onset of action, resulting in complete dissociative sedation within 2-5 min, and duration of action of 30-40 minutes, all while preserving respiratory drive. Ketamine is not contraindicated in the setting of head trauma and may, in some instances, be neuroprotective.[38, 39, 40, 41]

Comparison of prehospital ketamine vs haloperidol in agitated delirium has demonstrated more rapid onset of action and less need for re-dosing with ketamine. Adverse effects were more common with ketamine, mostly related to development of emergence reactions. The need for intubation in the ED setting with ketamine use is rarely reported and appears to be related to underlying medical pathology (intracranial hemorrhage, severe acidosis), higher doses (6 mg/kg IM) or repeated doses.[36] To date, no cases of death have been reported with prehospital or ED use of ketamine for sedation. edation. Still, midazolam remains a safer option and is a better choice for initial management of agitated delirium in the prehospital or ED settings.

Emergency Department Care

The general approach to hallucinogen-induced behavioral changes in the emergency department (ED) mirrors the recommendations for the prehospital setting as described above. As the ED is a potentially more controlled setting, fostering a calm and relaxed environment may obviate physical restraint and sedation. When possible, non-agitated patients should be placed in a quiet room with a one-to-one observer if available. Security personnel, physical restraints, and sedating agents should be prepared and readily available if agitation suddenly develops.

All patients should be evaluated for the presence of emergent medical conditions, including traumatic injuries, at the time of arrival. All patients should be placed on cardiac monitoring and have IV access established. Special attention should be paid to the patient’s temperature, as many hallucinogenic agents can induce hyperthermia, which may be life-threatening if not recognized early. An electrocardiogram should be considered as well, especially in the setting of abnormal vital signs, with attention to the QT interval.

Agitated behavior should be met with liberal doses of benzodiazepines. Haloperidol or droperidol may be useful adjuncts to benzodiazepines, but may associated with QT prolongation and torsade de pointes, decreased seizure threshold, or temperature dysregulation. The use of atypical antipsychotics should be avoided, as these agents could potentiate a serotonin syndrome. The use of ketamine in the ED has been shown to be extremely effective for behavioral control, especially to facilitate appropriate medical screening and trauma evaluations in agitated patients, though benzodiazepines are generally a safer option.[42]

Hyperthermia in patients with agitated delirium from a hallucinogen or other xenobiotic is an ominous and life-threatening emergency and should be managed aggressively. Phencyclidine, dextromethorphan, and the novel hallucinogenic agents have various degrees of stimulant qualities, which may produce marked hyperthermia due to temperature dysregulation and diffuse muscle fasciculation. Rapid initiation of cooling measures is mandatory and may require complete paralysis. Patients with extreme agitation should be given adequate hydration and watched closely for the development of rhabdomyolysis.

The above approach may be applied to any type of excited delirium and is not exclusive to hallucinogen-induced behavioral changes.

Consultations

Management of simple hallucinogen intoxication that resolves without intervention does not require specialty consultation. Patients may benefit from education information regarding drug addiction and local support groups at the time of discharge.

Patients who present with marked agitation, vital sign abnormalities or instability should be managed through a multidisciplinary approach between critical care specialists, medical toxicologists, and the regional poison control center (1-800-222-1222). While the exact agent causing the symptoms may not be known, clinical features and identification of specific toxidromes may help guide specific management.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents that may prove helpful include benzodiazepines and traditional antipsychotics.

Sedatives

Class Summary

Decrease agitation or combative behavior when patients are at risk of harming themselves or others.

Lorazepam (Ativan)

Sedative hypnotic with fairly rapid onset of effects (15-20 minutes) and relatively long half-life.

By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Haloperidol (Haldol)

Completely blocks postsynaptic dopamine receptors. Drug of choice for patients with acute psychosis when no contraindications are present. Has high potency and low potential for causing orthostasis. Downside is the high potential for extrapyramidal symptoms/dystonia, lowering of the seizure threshold, and QT-interval prolongation..

Parenteral dosage form may be admixed in syringe with 2-mg lorazepam for better anxiolytic effects.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation) by increasing activity of GABA.

Individualize dosage and increase cautiously to avoid adverse effects. Absorption is unpredictable with intramuscular administration, so should be used intravenously when possible.

Midazolam (Versed)

Sedative hypnotic with rapid onset and relatively short duration of effects.

By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

 

Follow-up

Further Outpatient Care

Patients with minimal or resolving symptoms can be discharged from the hospital safely. Advise these patients to avoid similar exposures and refer them to a behavioral health specialist for substance abuse evaluation. Discharge with medications is not indicated.

Further Inpatient Care

Patients with only minor agitation and adverse sympathomimetic effects can be safely treated in the ED with observation until symptoms have resolved.

Patients with hyperthermia, uncontrolled hypertension, seizures, or any evidence of cardiovascular instability should be admitted to a monitored patient care area. Consider consultation with a toxicologist or regional poison control center.

Obtain a psychiatric evaluation for patients with signs of persistent or severe psychotic behavior. Transfer patients for inpatient psychiatric care if psychiatric symptoms persist.

Inpatient & Outpatient Medications

Titration of benzodiazepines may be indicated to control agitation; administer phenothiazines only when indicated by severe psychotic reaction. Do not administer phenothiazines to patients with signs of sympathomimetic overstimulation. No outpatient medications should be required.

Transfer

Transfer patients with significant psychotic manifestations that are unresponsive to therapy, if appropriate behavioral health specialists are not available for evaluation. Exercise caution when transferring patients who demonstrate signs of continued intoxication.

Patient Education

For patient education information, see Club Drugs, Drug Dependence and Abuse, and Substance Abuse.