Howard A. Greller
Hallucinogens, from the Latin alucinari (to “wander in mind”), are a diverse class of xenobiotics that primarily alter sensory perception and interpretation, without altering orientation. The term hallucinogenis the medicolegal descriptor for this group of related compounds, whereas psychedelic is a common layperson descriptor. Hallucination is the perception of phenomena or objects that have no basis in reality (e.g., pink elephants). Visual hallucinations tend to have toxic metabolic causes, whereas auditory hallucinations tend to be primarily psychiatric or organic. The term hallucination contrasts with illusion, in which there is misinterpretation of a sensory perception (e.g., a coat hanging in a dark room is perceived as being a person). A synesthesia is a mixed perception (e.g., hearing color or seeing taste). Psychotomimetic describes a substance that causes psychological and behavioral changes resembling psychosis. An entactogen is a substance that enhances feelings of empathy, love, and emotional closeness and facilitates expression of emotions (e.g., methylene-dioxy-methamphetamine [MDMA]—ecstasy), whereas an entheogen(“generating the divine within”) is a psychoactive xenobiotic used in a ritualistic religious or spiritual context (e.g., 3,4,5-trimethoxyphenylethylamine—mescaline) (1).
Plant and animal species have been used in religious, spiritual, and other practices for centuries. The Rig-Veda, an Indian text more than 3,000 years old, praises soma, believed today to be the mushroom Amanita muscaria,containing the psychoactive compound muscimol (2,3). The modern era of hallucinogens had its origins with Albert Hofmann, who synthesized lysergic acid diethylamide-25 (LSD) in 1938. LSD was subsequently used as a therapeutic adjunct for psychotherapy but found its way into recreational use in the 1960s. As a result of concerns about birth defects and other toxicity, federal law in the mid-1960s banned LSD. Many hallucinogens are Food and Drug Administration (FDA) schedule I agents (4). In adolescents (age 12 to 17), overall hallucinogen use has declined in the 10-year period between 2002 and 2012 whereas the 18- to 25-year-old group had the highest prevalence of use within the last year. There has been a recent increase in the use of other hallucinogenic compounds, such as “foxy” (5-methoxy-N, N-diisopropyltryptamine), DMT (N, N-dimethyltryptamine), psilocybe mushrooms, phencyclidine (PCP), and ketamine (5).
The mechanism of hallucinogenesis has not been completely elucidated. Although derived from widely different sources and often chemically distinct, most hallucinogens share a structural similarity to serotonin (eFig. 346.1), and can be classified by structure. The tryptamine derivatives share the pyrrole structure of the indole ring. The amphetamine derivatives typically considered “hallucinogenic,” such as MDMA, share the methoxylated or methylenedioxylated catechol ring. Each of these structural features appears to be essential to hallucinogenic activity (1,3,6). The similarity of LSD and other hallucinogenic compounds to serotonin provides them with agonist activity at the 5-HT2 receptor. Specifically, the 5-HT2A-receptor subtype found predominantly on a population of postsynaptic neurons in the cerebral cortex has been implicated by functional studies in the modulation of hallucinations (7). Additional mechanisms for the generation of hallucinations include activity at the κ-opioid receptor, as is the case with Salvia divinorum and ibogaine (8), which are structurally unrelated to serotonin.
eFIGURE 346.1 Hallucinogenic compounds and their structural similarity to serotonin.
LSD is a semisynthetic lysergamide compound derived from the ergot fungus Claviceps purpurea. There are other naturally occurring analogs of LSD found in the seeds from plants of the morning glory family (Convolvulaceae), including the South American morning glory, the Mexican morning glory, and Hawaiian woodrose (2,9). LSD is very potent, with hallucinogenic doses in the range of a few hundred micrograms. It is most commonly administered through the oral route, generally as a fancifully designed blotter paper. The perforated paper defines a dosing unit, and the designs provide “branding.” Other forms include impregnated gelatin (“window panes”) or microdots (small pills or tablets), and occasionally as a liquid (4).
Mescaline, or 3,4,5-trimethoxyphenylethylamine, is a phenylethylamine compound that is derived from the peyote cactus (Lophophora williamsii). Although mescaline can be isolated from the cactus, this is a difficult process, and most of the time the compound is ingested in its natural form. Typically, a few of the small cactus crowns or “buttons” are removed, dried, and then ingested (4). The phenylethylamine analogs of mescaline are also used in an attempt to produce similar hallucinosis. Although the primary clinical effects of recreational doses of ecstasy (MDMA; see Chapter 348) do not involve hallucinations, hallucinations may occur at very high doses. The seeds of nutmeg (Myristica fragrans) are known to contain myristicin and elemicin, two mescaline-like substituted amphetamines with hallucinogenic properties (2,9). Up to 20 g of the ground spice need to be ingested to produce the hallucinatory effects, at the expense of significant gastrointestinal (GI) distress. Other phenylethylamine compounds include the “2 C” compounds including 2 C-B (4-bromo-2, 5-dimethoxyphenethylamine) and 2 C-T-7 (2, 5-dimethoxy-4-N-propylthiophenethylamine.)
The tryptamines are a group of structurally related compounds that produce hallucinosis. Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) and psilocin (4-hydroxy-N, N-dimethyl-tryptamine) are two compounds of the indolalkylamine class isolated from mushrooms of the Psilocybe genus (1,2,9). The two most common species are the “liberty cap” (Psilocybe semilanceata) and Psilocybe cubensis. The spores of these mushrooms are not considered a controlled substance (although the mature mushrooms are), are readily available through a variety of sources, and are easy to grow into mature mushrooms. Being a natural product, the amount and type of hallucinogenic compound contained within any singular mushroom vary widely, and therefore there is no “typical” dose (see Chapter 354).
“Foxy” or “foxy methoxy” (5-methoxy-N, N-diisopropyltryptamine, 5-MeO-DIPT) and α-methyltryptamine (AMT) are tryptamine derivatives (1,4,5). Both drugs are available as capsules filled with powder and are orally bioavailable. DMT (N, N-dimethyl-tryptamine) is a tryptamine derivative of the Yakee plant (Virola calophylla). Ayahuasca is a psychotropic plant that is used as a tea throughout the Amazon basin in traditional medicine and shamanistic practices. Ayahuasca is made by steeping the pounded stems of the vine Banisteriopsis caapi alone or in combination with the leaves of Psychotria viridis. This combination is ethnopharmacologically interesting because P. viridis contains DMT and B. caapi contains alkaloids such as harmine and tetrahydroharmine. DMT is normally metabolized by GI monoamine oxidase (MAO), and harmine and the other β-carboline alkaloids are MAO inhibitors (1,2,9). Thus the combination of the two plants allows for the increased bioavailability of the DMT.
Secretions of the modified parotid gland of the Colorado River toad, Bufo alvarius, contain a mixture of “defensive” chemicals designed to protect from predators. These chemicals include catecholamines, cardioactive steroids, and bufotenine (5-methoxy-N, N-dimethyltryptamine, 5-MeO-DMT), a potent hallucinogenic compound. People engage in the practice of “toad-licking” in attempts to experience the psychedelic properties of this chemical. This practice is often complicated with the consequences of the other compounds contained within the secretions, most notably cardioactive digoxin-like steroids (see Chapter 325) (1).
S. divinorum, a member of the mint family, has been used for centuries by the Mazatec Indians of Oaxaca, Mexico. The active compound is a neoclerodane diterpene, salvinorin A, structurally unrelated to any of the previously described hallucinogenic compounds and believed to exert its clinical effects through action at the κ-opioid receptor. S. divinorum is taken orally, with rapid oral–mucosal absorption, and by smoking (5,8).
Ibogaine is derived from the root of the Tabernanthe iboga plant, found primarily in West African nations. Ibogaine has gained recent attention as a potential treatment for addiction to compounds such as cocaine and heroin and is being investigated by the FDA for such purposes. Ibogaine is taken orally (2,4,5,9).
CLINICAL PRESENTATION
Unlike most other drugs of abuse, users of hallucinogens rarely present acutely to the healthcare provider (4,5). Hallucinogens in general have few significantly dangerous adverse side effects, and patients generally present to the emergency department (ED) for secondary reasons (e.g., trauma) or for “bad trips.” The unique nature of hallucinogens defines their clinical presentation. Unless combined with other drugs, patients should be alert and fully oriented and able to give a history of use. A clear sensorium is a key historical and examination point, suggesting the use of LSD. This contrasts with drug-induced delirium, such as that associated with PCP, in which, by definition, the patient’s orientation is altered. In addition, in an attempt to obtain a hallucinogen, patients are commonly exposed to more sympathomimetic compounds (such as 25I-NBOMe) and have more physiologic derangements.
Hallucinations or illusions are alterations in the perception of time and body image and changes in the interpretation of sensory information. Hallucinogenic experiences are commonly referred to as a “trip,” and the experience tends to be an extremely personal one. The perceptual changes that users perceive can affect any of the senses: hearing, taste, smell, touch, or sight. The person can experience exaggeration, diminution, or mixing (synesthesias) of their sensory perception. The users’ sense of time may be altered, generally slowed, as may their sense of space. Body dysmorphisms are common, in which personal physical features take on abnormal proportions. Events can be perceived as hyperreligious or evil. Additional clues to the diagnosis include the sympathomimetic effects of some of the compounds involved, although these effects are usually mild and rarely dangerous. Common physical signs and symptoms of acute intoxication include mydriasis, diaphoresis, piloerection, tremors, and mildly elevated blood pressure, pulse, respiratory rate, and temperature. These findings may be masked by the coingestion of ethanol or other sedative–hypnotic agents.
Injury is the predominant adverse event related to hallucinogen use, as a result of the acute behavioral effect of the drug. There are few, if any, dangerous physiologic effects of the drugs themselves. The psychological effects can be overwhelming, and occasionally the hallucinations can be perceived as frightening or threatening (“bad trips”) causing the patient to panic or respond in a manner causing injury. These experiences can include or engender paranoia, acute psychosis, panic, and significant depression. Suicide and unintentional death have been reported (2,5). There is no withdrawal syndrome from hallucinogens, although tolerance and crosstolerance between compounds can occur.
Mescaline use is associated with significant, unpleasant side effects. Initial signs and symptoms include nausea, vomiting, abdominal pain, diaphoresis, nystagmus, and ataxia. These symptoms typically resolve within 1 to 2 hours of ingestion and precede the onset of the hallucinations, which begin within 4 to 6 hours and typically last for 6 to 12 hours (5).
Hallucinogenic doses of nutmeg cause severe side effects, such as dizziness, flushing, tachycardia, nausea, vomiting, constipation, and panic. Because of the relative severity of the side effects, it is not a popular means of producing hallucinations. When ingested, the hallucinations begin within 1 to 4 hours and last 12 to 24 hours. Many users report an extended period of sleep after use (upward of 16 hours).
Ingestion of psilocybe mushrooms is typically associated with nausea and sometimes vomiting. Onset of effect is approximately 30 minutes, and the duration is typically 4 to 6 hours. The effects are described as being typically “less intense” and more illusionary than those produced by LSD (1,2,9). AMT has a longer duration of effect (approximately 12 to 24 hours) than that of Foxy (between 3 and 6 hours). Toad licking has resulted in digoxin-like bradycardia and significant adverse effects from other components of toad secretions (1).
The hallucinogen persisting-perception disorder (HPPD), commonly known as “flashbacks,” associated with the use of LSD should not be confused with prolonged sensory perception (afterimages), also known as palinopsia. Patients with HPPD characteristically experience, in the absence of the drug, recurrent perceptual disturbances similar to those encountered during acute intoxication. HPPD is often triggered by stress, illness, or other challenges. HPPD can occur after a single use of the drug and may last for a prolonged period (up to years) (1,10). HPPD is associated with the use of phenothiazine antipsychotics to control the acute behavioral symptoms of acute intoxication, suggesting that sedatives such as benzodiazepines, rather than antipsychotics, should be used for this purpose. Proposed therapies for HPPD include clonazepam, carbidopa, and psychotherapy. A rare reported adverse effect of LSD is permanent psychosis (10).
The time of onset and duration of effect can help determine the identity of the hallucinogen (see Table 346.1). Long-acting agents include LSD, mescaline, and nutmeg. Medium-acting agents include psilocybin, psilocin, Foxy, AMT, and Bufo sp–toad toxins. Short-acting hallucinogens include DMT, ibogaine, and salvinorin A.
TABLE 346.1
Common Hallucinogenic Compounds
Smoking DMT leads to effects that typically begin within minutes and last between 30 and 60 minutes. Rapid onset and short duration of action has earned DMT the moniker “the businessman’s lunch,” because the user can experience a “trip” in the time allotted for a meal (1,4,5). Following the ingestion of ayahuasca, DMT also has a rapid onset of action and short duration of effect (1,2,9).
The ingestion of S. divinorum produces effects that begin in 5 to 10 minutes and last approximately 1 to 2 hours. When the vapor is inhaled or the plant is smoked, effects begin in seconds and last about 30 minutes (5,8). Ibogaine ingestion can cause both early (4 to 8 hours after ingestion) and late (10 to 20 hours after ingestion) hallucinations (2,4,5,8).
DIFFERENTIAL DIAGNOSIS
Other abused agents that can cause hallucinations include sympathomimetics, anticholinergics, and dissociative anesthetic agents and related compounds. Cocaine and amphetamines are associated with psychosis at high doses or following binges and those atients characteristically develop a delusional state that does not always involve clear hallucinations. Symptoms may last for several days but typically respond to antipsychotic medications. Anticholinergic agents (e.g., scopolamine and atropine) may produce dramatic epidemic hallucinations when teenagers discover Jimsonweed (Datura stramonium) and ingest the seeds. Patients generally have other manifestations of the anticholinergic syndrome and are almost always delirious. Dissociative anesthetic agents, such as PCP, ketamine, and the related compound dextromethorphan, produce hallucinations that are generally described as dysphoric which can cause wild and unreasoned behavior. Clinical features include delirium and prominent nystagmus. Autonomic manifestations are usually more prominent than hallucinations in each of these conditions. In contrast, with traditional hallucinogens such as LSD, hallucinations are prominent, and autonomic effects are usually mild.
Hallucinations have been reported as idiosyncratic reactions to almost all medications. Street-drug adulterants (e.g., cyanide, local anesthetics, quinine, quinidine, caffeine, theophylline, and strychnine) should be considered in the differential of hallucinosis. Because central nervous system (CNS) structural, infectious, and psychiatric conditions can cause hallucinations, exposure to a hallucinogenic agent should be a diagnosis of exclusion. With or without the history of hallucinogen exposure, these conditions should always be considered in the differential diagnosis.
ED EVALUATION
The history from family, friends, or the patient, who is usually cooperative and oriented, should include the name or description of the hallucinogen, the time of ingestion, amount(s) taken, the route of exposure, and the nature and time of onset of hallucinations and other symptoms. Slang names may provide a presumptive identity, if the chemical name is not known. A history of previous drug use, psychiatric problems, and medical conditions, particularly cardiovascular disease, should be documented. The clinician should specifically explore the possibility of concomitant traumatic injuries.
The physical examination should focus on the mental status, neurologic evaluation, and cardiovascular system. Vital signs documented and repeated frequently. The patient should be examined carefully for evidence of trauma, underlying disease, and heat-related illness.
Ancillary testing is neither necessary nor useful in patients with mild hallucinogen intoxication, except to rule out other diagnoses. Patients with moderate or severe symptoms (e.g., excessive agitation and significantly abnormal vital signs) should have a chest radiograph; cardiac monitoring and a 12-lead electrocardiogram (ECG); complete blood count; determination of electrolyte, glucose, blood urea nitrogen, creatinine, and creatine kinase levels; and urinalysis performed to exclude other conditions or exposures. Significant psychomotor agitation can occur with a variety of perceived stimuli, and rhabdomyolysis should be considered. Routine toxicology screens are rarely sensitive or specific enough to provide confirmation or exclusion of another agent as the causative etiology of a specific clinical presentation. Quantitative blood (or urine) hallucinogen levels are not clinically useful or routinely available.
KEY TESTING
• Rapid glucose measurement and core temperature are useful in all patients
• ECG and other tests as needed for supportive care or to exclude other causes
• Radiographs to evaluate suspected trauma
ED MANAGEMENT
Management is supportive. Standard life-support measures should be instituted as needed, but an intravenous line is often not needed. The focus of care should then be to provide a calm, quiet environment for the patient. Providers should attempt to reduce the patient’s anxiety, help to provide a foundation for reality testing, and provide continued, empathetic reassurance. In cases in which the experience is causing the patient significant agitation or distress, pharmacologic sedation with a benzodiazepine should be provided. Phenothiazines should be avoided because they have been implicated in HPPD (10). Although activated charcoal can bind most, if not all, of these compounds, the efficacy of this intervention is undefined. Because consequential morbidity is exceedingly rare and because GI decontamination may be particularly unpleasant for a patient who is hallucinating, its use is unnecessary except for patients with significant coingestions.
CRITICAL INTERVENTIONS
• Provide a calm, quiet environment with continuous observation and repeated reassurance.
• Administer benzodiazepines for persistent or severe agitation or psychological distress.
DISPOSITION
For the majority of patients presenting after use of a hallucinogen, their disposition will be discharged. In the absence of any adverse sequelae (e.g., trauma, rhabdomyolysis, electrolyte abnormality, etc.), the patient should be watched until reality testing is assured, and appropriate referral to a psychiatrist or substance abuse program can be provided. Admission is warranted only for persistence of psychosis or if the patient has a concomitant medical or surgical issue that makes this necessary.
ACKNOWLEDGMENTS
The author gratefully acknowledges the contributions of Lewis S. Nelson and Christopher H. Linden to previous editions of this chapter.
Common Pitfalls
• Failure to obtain a complete set of vital signs, especially an accurate core temperature.
• Failure to differentiate between hallucinations and delirium; patients with drug-induced hallucinations have clear orientation with altered content.
• Failure to make safety of the patient and staff a priority.
• Failure to consider metabolic, structural, infectious, traumatic, and psychiatric etiologies of the hallucinatory state.
• Failure to screen for occult conditions caused by the behavioral abnormalities of these compounds, such as rhabdomyolysis.
• Failure to consider coingestants or nonclassical hallucinogen-producing compounds (i.e., anticholinergic agents) and their specific toxicities.
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