82: Hallucinogens

A “hallucination” may be defined as a false perception that has no basis in the external environment. The term is derived from the Latin term meaning “to wander in mind.” While the term “psychedelic” has been used for years to refer to the recreational and nonmedical effects of hallucinogens, other terms, like entheogen and entactogen, frequently appear in Internet discussions. Entheogens are “substances which generate the god or spirit within,” while entactogens create an awareness of “the touch within.”⁴¹ These terms all refer to the same xenobiotics, used with differing intent or in varying settings. Hallucinations differ from illusions, which are distorted perceptions of objects based in reality.

Hallucinogens are a diverse group of xenobiotics that alter and distort perception, thought, and mood without clouding the sensorium. Hallucinogens can be categorized by their chemical structures, and further divided into natural and synthetic members of each family. The major structural classes of hallucinogens include the lysergamides, tryptamines (indolealkylamines), amphetamines (phenylethylamines), arylhexamines, cannabinoids, harmine alkaloids, belladonna alkaloids, and the tropane alkaloids. In addition, there are several unique hallucinogens, such as Salvia divinorum, nutmeg, kratom, and kava kava. This chapter focuses on lysergamides, tryptamines, phenylethlyamines, and the unique hallucinogens. More on the other classes can be found in Chaps. 73, 76, 77, 78, and 86.

Hallucinogens have been used for thousands of years by many different cultures, largely during religious ceremonies. The ancient Indian holy book, Rig-Veda, written more than 3500 years ago, describes a sacramental substance called Soma both as a god and as an intoxicating substance. Although debated for many years, the source of Soma is now believed to be an extract of the mushroom Amanita muscaria.^101,108 The Aztecs used the psilocybin-containing teonanacatl (flesh of the gods) and Ololiuqui (morning glory species) in their religious ceremonies. To this day, the Native American Church in the United States uses peyote in religious ceremonies.

From medieval times through recent years, several large-scale epidemics of vasospastic ischemia, gangrene, and hallucinations (collectively called ergotism) have resulted from Claviceps purpurea contamination of cereal crops.¹³⁶ The hallucinations from Claviceps ingestion are attributed to the ergot alkaloid lysergic acid amide from which lysergic acid diethylamide (LSD) was chemically synthesized. Claviceps purpurea has been suggested, but subsequently disproved, as the cause of the mass hysteria leading up to the Salem witch trials. Many of these adverse effects after ingestion of C. purpurea have been attributed to the serotonergic agonist effects of the ergot alkaloids (Chap. 54).³⁸

Synthetic hallucinogen use is often said to have begun in 1938 when Albert Hofmann, a Swiss chemist, synthesized LSD while performing extensive research on the medicinal uses of ergot alkaloids derived from the fungus, C. purpurea. Five years later, LSD was “tested” when Hofmann exposed himself in his laboratory and subsequently developed hallucinations.^63,120 Soon thereafter, Sandoz Laboratories began marketing LSD under the trademark Delysidas an adjunct for analytic psychotherapy. In the 1950s, a small number of psychiatrists began using LSD to release the repressed memories of patients, and as an experimental model for schizophrenia.¹²⁷ The US Central Intelligence Agency reportedly experimented with the use of LSD as a tool for interrogating suspected communists and as a mind-control agent.^23,120

In the 1960s, the concept of the “fifth freedom” emerged. As individuals explored this “right” to alter their consciousness as they saw fit, LSD (also called acid) became a fashionable recreational drug. In one of the most famous slogans of the 1960s, Dr. Timothy Leary popularized LSD as a way to “Tune in, Turn on, Drop out.”¹²⁰ By 1966, US federal law banned the use of LSD.⁹⁴ Initial reports of LSD-induced chromosomal damage appeared in the 1960s.^32,65,76 However, further studies of pregnant women who had taken LSD did not demonstrate an increased risk of abortions or birth defects.^44,73

LSD use diminished in the late 1970s and early 1980s, perhaps due to user concerns regarding potential health risks of brain damage, “bad trips” and flashbacks.¹⁰⁰ In the meantime, there was a rise in the use of the “designer” hallucinogens. Exploiting a loophole in drug enforcement laws, these designer synthetic tryptamine and amphetamine hallucinogens are chemically similar to, but legally distinct from, their outlawed counterparts and therefore not subjected to legislative drug control. These are often referred to as “legal highs.” The Internet has developed as a vehicle for the rapid and facile sharing of information on the synthesis of emerging drugs, user experiences, and adverse effects. Additionally, the Internet marketplace has made many “herbal” hallucinogens widely available via unregulated Web sites.³⁶ All-night dance clubs host “rave parties,” at which emerging hallucinogens are popular.¹³ While the impact of these parties on the growth of hallucinogens in the United States is unclear, many of the newer hallucinogens have been christened “club drugs” because of this association.⁵³

Resurgence in LSD use was reported among high school teens in the late 1990s, with more prevalent use in the suburbs than the city.^95,109 In 1997, two studies of adolescents showed a lifetime prevalence of LSD use at 13% and 14%.^67,100 In 2000, US Drug Enforcement Agency (DEA) agents seized an LSD-production lab and apprehended two men involved in massive production of LSD in Kansas City. Their incarceration resulted in a more than 90% decrease in LSD availability nationwide.

While much of the research involving psychedelic drugs was halted in the 1960s, there has been a reemergence of clinical investigations since the late 1980s for the treatment of various psychiatric disorders, with emphasis on treatment of anxiety and addictions. Recently, psilocybin has been evaluated for the treatment of the existential anxiety associated with end-stage cancer and obsessive-compulsive disorders, while 3,4-methylenedioxymethamphetamine (MDMA) has been studied as an adjunct to psychotherapy for treatment-resistant posttraumatic stress ­disorder.^57,89,90 The clinical or research use of psychedelic drugs remains highly controversial.

The 2006 National Survey on Drug Use and Health (NSDUH) reported the following trends in hallucinogen use: more than 23 million Americans older than 12 years of age reported LSD use during their lifetime, 6.6 million had used phencyclidine (PCP), and 12 million reported previous MDMA use. Additionally, 2.3 million people reported prior use of ketamine, while only 700,000 reported use of α-methyltryptamine (AMT), dimethyltryptamine (DMT), or 5-methoxydimethyl tryptamine (5-MeO-DMT). About 1.8 million people reported use of Salvia divinorum during their lifetime. In the reported results, the 18 to 25 year-old age group was most likely to report use of any of these hallucinogens within the previous year (Table 82–1).¹²² In 2010 the NSDUH reported that 1.2 million Americans older than 12 years of age were current users of hallucinogens.¹²⁸

Lysergamides are derivatives of lysergic acid, a substituted tetracyclic amine based on an indole nucleus (Fig. 82–1). Naturally-occurring lysergamides are found in several species of morning glory (Rivea corymbosa, Ipomoea violacea) and Hawaiian baby woodrose (Argyreia nervosa).⁵⁹ Morning glory seeds contain multiple alkaloids, including lysergic acid, hydroxyethylamide, and ergonovine. Morning glory seeds were called ololiuqui in ancient Mexico, where Aztecs and other indigenous populations used them in religious rites.¹²⁴ However, in one volunteer study, ololiuqui caused sedation rather than hallucinations.⁶⁴ Hawaiian baby woodrose seeds contain ergine. Both morning glory and Hawaiian baby woodrose seeds can be legally purchased for planting in garden stores and on the Internet.

The synthetic lysergamide, LSD, is derived from an ergot alkaloid of the fungus, Claviceps purpurea. Although four LSD isomers exist, only the d-­isomer is active. Lysergic acid diethylamide is a water-soluble, colorless, tasteless, and odorless powder. Currently, LSD is typically sold as liquid-impregnated blotter paper, microdots, tiny tablets, “window pane” gelatin squares, liquid, powder, or tablets.¹⁰⁹ LSD users typically experience heightened awareness of auditory and visual stimuli with size, shape, and color distortions. Auditory and visual hallucinations may occur, as well as synesthesia, a confusion of the senses, where users may report “hearing ­colors, or seeing sounds.” Other more complex perceptual effects may include depersonalization and a sensation of enhanced insight or awareness. A “bad trip” is said to occur when LSD use produces anxiety, bizarre behaviors, and combativeness.

LSD is classified by the DEA as a Schedule I agent, with high abuse potential, lack of established safety even under medical supervision, and no known use in medical treatment.

Indolealkylamines, or tryptamines, represent a class of natural and synthetic compounds that structurally share a substituted monoamine group (Fig. 82–2). Endogenous tryptamines include serotonin and melatonin. Naturally occurring exogenous tryptamines include psilocybin, bufotenine, and DMT. Psilocybin is found in three major genera of mushrooms: Psilocyba, Panaelous, and Conocybe.¹⁰⁸ Other psychoactive mushrooms include Amanita muscaria and Amanita pantherina, which contain ibotenic acid, muscimol, and muscazone, which are unrelated to the tryptamines.⁵⁹ Hallucinogenic mushrooms are discussed at length in Chap. 120. Psilocybin-containing mushrooms, or “magic mushrooms,” grow in the Pacific Northwest and southern United States, usually in cow pastures. The mushroom may be recognized by a green-blue color that it assumes after bruising, but misidentification is common.¹¹

N,N-dimethyltryptamine (DMT) is a potent short-acting hallucinogen found naturally in the bark of the Yakee plant (Virola calophylla), which grows in the Amazon basin. It is used by shamans as a hallucinogenic snuff to “communicate with the spirits.”¹⁰⁸ DMT is also found in the hallucinogenic tea, ayahuasca, which is used by indigenous healers in the Amazon Basin. In ayahuasca, DMT-containing plants (eg, Psychotria viridis) are combined with plants containing harmine alkaloids (eg, Banisteriopsis caapi), which inhibit hepatic monoamine oxidases to increase the oral bioavailability of DMT (Chap. 73).⁸⁵

The use of toads in religious ceremonies and witchcraft dates back thousands of years. All species of the toad genus Bufo have parotid glands on their backs that produce a variety of substances, including dopamine, epinephrine, and serotonin.⁷⁸ Some of these toads produce bufotenine, a tryptamine, which causes hypertension, but does not cross the blood–brain barrier. Interest in bufotenine grew out of reports of a toad-licking fad in the 1980s, in which individuals would reportedly lick toads for recreational purposes.⁷⁷ However, further review suggests that bufotenine is not the hallucinogenic substance found in toad secretions. Instead, 5-MeO-DMT has been identified as the psychoactive substance.¹³⁵ 5-MeO-DMT is only found in one species of toad, Bufo alvarius (Sonoran Desert toad or Colorado River toad).⁷⁷ Although bufotenine has been classified as a Schedule I substance by the DEA for many years, 5-MeO-DMT was not scheduled until 2009.⁹¹ Like DMT, 5-MeO-DMT is rapidly metabolized by intestinal monoamine oxidase enzymes; oral ingestion of toad venom or skins would thus have limited potential as a route of recreational use.²¹ Methods for extracting and drying B. alvarius secretions for smoking and insufflation are available on the Internet. Death has resulted from wrongful use of Bufo secretions for purposes of aphrodisia.^30,55 The toad venom glands also produce cardioactive steroids, called bufadienolides, which cause digoxinlike cardiac toxicity, and in some species, can secrete tetrodotoxin.^87,139

Two of the more important synthetic tryptamines include N,N-diisopropyl-5-methoxytryptamine (5-MeO-DiPT, Foxy Methoxy) and α-methyltryptamine (AMT, IT-290). Since 2001, law enforcement authorities in more than 10 states have seized large amounts of 5-MeO-DiPT and AMT. These drugs are often sold surreptitiously as MDMA. 5-MeO-DiPT received Schedule I status in 2004.¹³⁰ α-Methyltryptamine (AMT or IT-290) is a monoamine oxidase inhibitor that was sold as an antidepressant in the ­former Soviet Union.¹¹⁴ AMT was placed into Schedule I status by the DEA in September 2004.¹³⁰

Dopamine, norepinephrine, and tyrosine are endogenous phenylethylamines. Exogenous phenylethylamines stimulate catecholamine release and cause a variety of physiologic and psychiatric effects, including hallucinations. Substitution on the phenylalkylamine structure has important effects on both the hallucinogenic and stimulant potential of the drug. The presence of a methyl group in the side chain of the phenylethylamines is associated with a higher degree of hallucinogenic effect (Fig. 82–3).⁶⁹ MDMA, amphetamine, and methamphetamine are well known members of this family and are discussed in detail in Chap. 76.

The best recognized of the naturally occurring psychoactive phenylethylamines is mescaline. Mescaline is found in Peyote (Lophophora williamsii), a small blue-green spineless cactus that grows in dry and rocky slopes throughout the southwestern United States and northern Mexico. Peyote buttons are the round, fleshy tops of the cactus that are sliced off and dried. The legal use of peyote in the United States is restricted to members of the Native American Church, for whom peyote buttons are used for both religious ceremonies and medical treatment for physical and psychological ailments.^24,27

Other nonindigenous cactus species containing significant amounts of mescaline include the San Pedro cactus (Trichocereus pachanoi) and Peruvian torch cactus (Trichocereus peruvianus). These plants can be purchased for ornamental purposes in garden stores and on the Internet.⁵⁹

The synthesis and effects of hundreds of other congeners of amphetamine is well described.¹¹³ Included are the synthetic hallucinogenic amphetamines 4-bromo-2,5-dimethoxyphenethylamine (2C-B, Nexus, Bromo, Spectrum) and 2,5-dimethoxy-4-N-propylthiopheneethylamine (2C-T-7, Blue Mystic).

During the 1980s, 2C-B gained popularity as a legal alternative to MDMA. When 2C-B was given Schedule I status in 1995, 2C-T-7 emerged as another legal designer amphetamine.⁹ In March 2004, 2C-T-7 also received Schedule I status.³⁴

Salvia divinorum is a perennial herbaceous member of the mint family. While there are more than 500 species of Salvia, S. divinorum is most recognized for its hallucinogenic properties.¹³¹ Salvia divinorum is a native to areas of Oaxaca, Mexico, and grows well in sunny temperate climates. Plants, leaves, and extracts may be purchased online, and tips for cultivation of plants are easily accessible.

Since the sixteenth century, the Mazatec Indians have used S. divinorum as a hallucinogen in religious rites as a means of producing “visions.”¹³¹ The Mazatecs continue to revere S. divinorum as an incarnation of the Virgin Mary, referring to the plant as “ska Maria.” Currently, although the federal Controlled Substances Act does not prohibit use of S. divinorum or its psychoactive extracts, the possession and sale of S. divinorum is illegal in several states, including Delaware, Florida, and Georgia. Nationwide regulation of this substance exists in Australia, and there is local regulation in some municipalities where S. divinorum use among teenagers is rampant.¹²⁹ There continues to be widespread marketing of this hallucinogen on the Internet as a “legal hallucinogen.”

Kratom, or Mitragyna speciosa Korth, is derived from the leaves of a tree native to Asia and Africa.¹¹² Kratom has dual properties, producing stimulant effects and opioidlike analgesic effects. It was used in Southeast Asia to enhance productivity in manual laborers. The Kratom alkaloids mitragynine and 7-hydroxymitragynine activate µ-, δ-, and κ-opioid receptors. It has been used as a substitute for opium, although hallucinogenic effects are uncommon, they are reported following heavy use.¹²³ Kratom has been illegal in Thailand since 1946 and in Australia since 2005. Kratom is currently legal to possess and use in the United States, where it has been adopted by some patients for self-treatment of chronic pain and to modulate opioid withdrawal symptoms.

Nutmeg is derived from Myristica fragrans, an evergreen tree native to the Spice Islands. The fruits of the tree contain a central kernel called the nutmeg, while the surrounding red aril is used to produce a spice called mace.⁹⁹ While nutmeg is commonly available as a cooking spice, it has been used medicinally for centuries as an antidiarrheal and abortifacient.⁵⁸ It is a recreational herbal that has also been used to produce euphoria and hallucinations; it is more likely to be abused by adolescents due to its low cost and accessibility.^35,99,105

The belladonna alkaloids, including the tropane alkaloids atropine, hyoscyamine, and scopolamine, can be isolated from a number of plants. Deadly nightshade (Atropa belladonna), a perennial plant, grows throughout the United States, as well as in areas of Europe and Africa. Belladonna alkaloids can be isolated from both the leaves and berries of this perennial plant. Jimson weed (Datura stramonium), also called locoweed, grows throughout warm and moist areas of the world. This bush contains pods full of small black seeds that are ingested or brewed as a tea for their hallucinogenic properties. The common name Angel’s trumpet is used for plants of the Solanaceae family with large trumpet-shaped white flowers (Brugmansia or Datura). Given their wide availability, in the wild and over the Internet, these plants are frequently used as hallucinogens by adolescents.⁵⁴ Unfortunately, they produce significant morbidity from anticholinergic toxicity in unwary users. Moonflower, a common name given to several plants, including Datura inoxia, was responsible for anticholinergic poisoning of more than a dozen adolescents in one series.³¹ Additionally, epidemics of unintentional poisoning were reported among drug users who received heroin adulterated with scopolamine.⁶¹

LSD is the most studied hallucinogen, and there is extensive information about its pharmacokinetics (Table 82–2). Ingestion is the most common route of exposure, and the gastrointestinal tract rapidly absorbs LSD. Other reported routes of administration include intravenous, intramuscular, intranasal, parenteral, sublingual, inhalation, and conjunctival instillation. Plasma protein binding is more than 80% and volume of distribution is 0.28 L/kg. It is concentrated within the visual cortex as well as the limbic and reticular activating systems. It is metabolized in the liver via hydroxylation and glucuronidation, and excreted predominantly as a pharmacologically inactive compound. LSD has an elimination half-life of about 2.5 hours. Only small amounts are eliminated unchanged in the urine. The minimum effective oral dose is 25 µg.⁷⁰ The onset of effects may occur 30 to 60 minutes after exposure, with a duration of 10 to 12 hours.

Ingestion of 200 to 300 morning glory seeds is required to achieve hallucinogenic effects. Only 5 to 10 seeds of Hawaiian baby woodrose are required to produce hallucinations. After ingestion of woodrose seeds, the effects typically last for 6 to 8 hours and produce tranquility without marked euphoria.⁴

Peyote buttons are very bitter, and can be eaten whole or dried and crushed into a powder, which is reconstituted as tea.⁵⁹ Nausea, vomiting, and diaphoresis often precede the onset of hallucinations, which begin at 1 to 3 hours postingestion, and last for up to 12 hours.⁹⁹ Six to twelve peyote buttons, or 270 to 540 mg of mescaline, are commonly required to produce hallucinogenic effects.¹⁰⁷ Ingestion of up to 5 g of psilocybin-containing mushrooms may be required to produce hallucinogenic effects. After ingestion of Psilocybe mushrooms, psilocybin is converted to psilocin, the active hallucinogen in the gastrointestinal tract.⁵⁶ The effects of psilocin are similar to LSD, but with a shorter duration of action of about 4 hours.

For recreational purposes, DMT is typically smoked, snorted, or injected. Hallucinogenic effects peak in 5 to 20 minutes, with a duration of 30 to 60 minutes, earned DMT the nickname the “businessman’s trip.” 5-Meo-DiPT is most commonly ingested, but may be smoked or insufflated. Effects begin 20 to 30 minutes after ingestion, and include disinhibition and relaxation. There is a dose-dependent response and at higher ranges, symptoms include mydriasis, euphoria, auditory and visual hallucinations, nausea, diarrhea, and jaw clenching.^93,115 The hallucinogenic effects are reported to last from 3 to 6 hours.^86,115 Other substances may be used to heighten or prolong the hallucinogenic effects of 5-MeO-DiPT. These include sildenafil, γ-hydroxybutyrate, benzodiazepines, and marijuana. AMT is available as a white powder, which may be ingested, smoked, or insufflated. Hallucinations typically occur within 30 minutes, but may last 12 to 16 hours.⁷⁵

Amphetamine, methamphetamine, and MDMA are well absorbed through the gastrointestinal tract. The elimination half-life ranges from 8 to 30 hours for members of this class and is dependent on urine pH.^12,33 Amphetamines are weak bases and undergo more rapid elimination in acidic urine.¹¹⁰ The volume of distribution ranges from 3 to 5 L/kg for amphetamine, 3-4 L/kg for methamphetamine, and likely more than 5 L/kg for MDMA.^12,33,74,110 Elimination of other amphetamines occurs through multiple mechanisms including aromatic hydroxylation, aliphatic hydroxylation, and N-dealkylation.⁷⁴ Tolerance occurs with chronic amphetamine use.⁷¹

There is little information about 2C-B and 2C-T-7 in the medical literature. Both drugs may be used via oral, intranasal, and intrarectal routes. Both 2C-B and 2C-T-7 exert their hallucinogenic effects within one hour of use, and physiologic and psychologic effects may persist for 6 ot 10 hours. Additional information on the kinetics of amphetamine and congeners may be found in Chap. 76.

Salvia divinorum may be chewed, smoked, or ingested as tea. Hallucinations occur immediately after exposure to the drug and are typically quite vivid. Synesthesia is reported among Salvia users. Hallucinogenic effects after S. divinorum use are typically brief, lasting only 1 to 2 hours. Pharmacokinetic data for S. divinorum, and its primary psychoactive, Salvinorin A, were described in one volunteer study.¹¹⁶ Psychoactive effects were typically experienced 5 to 10 minutes after absorption of Salvinorin A via the buccal mucosa, reaching a plateau during the first hour after exposure and resolving within 2 hours. Vaporization and inhalation of Salvinorin A led to more rapid effects beginning at 30 seconds after exposure. These effects would plateau at 5 to 10 minutes and typically subside after 20 to 30 minutes. In this study, ingestion of S. divinorum leaves did not produce the same effects as buccal or inhalational administration, leading to the theory that gastrointestinal deactivation of Salvinorin A occurs after ingestion.¹¹⁶

Kratom leaves can be decocted into tea, chewed, or smoked.⁶⁶ Kratom leaves contain approximately 0.8% mitragynine by weight, but can vary by geographic origin of trees, as well as season.¹¹¹ Neuropsychiatric effects are dose dependent and occur within 5 to 10 minutes of exposure, with effects lasting 4 to 6 hours.¹²³ Stimulant effects predominate at doses of 2 to 6 g, while sedation becomes more pronounced at doses above 7 g.

Nutmeg is usually ingested as a paste, or mixed in a beverage; 15 to 20 g of the substance is required for clinical effects.⁹⁹ This dose is often unpalatable, and a case report of recreational use of encapsulated nutmeg has been described.¹⁰⁵ Clinical effects can begin 1 hour after nutmeg ingestion; nausea and vomiting precede the onset of hallucinations, and effects can persist for more than 24 hours after exposure.⁹⁹

The belladonna alkaloids are most concentrated in the seeds of Jimson weed; each seed contains approximately 0.1 mg of atropine.¹¹⁸ Ingestion of as few as 10 seeds can produce hallucinations within 20 to 30 minutes; these effects can last for 2 to 3 hours. While the roots and seeds of Angel’s trumpet contain the highest alkaloid concentrations, users most often brew the blossom into a tea. Each blossom contains approximately 0.3 mg of atropine and 0.65 mg of scopolamine.⁵⁴ The elimination half-lives of atropine and hyoscyamine are 2.5 and 3.5 hours, respectively, while the elimination half-life of scopolamine is considerably longer, at 8 hours.¹⁵

Although the lysergamide, indolealkylamine, and phenylethylamine hallucinogens are structurally distinct, the similarities in their effects on cognition support a common site of action on central serotonin receptors.^{3,20,26,62,126} Serotonin (5-HT) modulates many psychological and physiologic processes, including mood, personality, affect, appetite, motor function, sexual activity, temperature regulation, pain perception, sleep induction, and ADH release. There are more than 14 known 5-HT receptor subtypes (Chap. 14); differing affinity for these subtypes occurs based on the structure of the hallucinogen, and may account for the subtle differences between their effects.

The lysergamide, indolealkylamine, and phenylethylamine hallucinogens all bind to the 5-HT₂ class of receptors. There is good correlation between the affinity of both indolealkylamine and phenylethylamine hallucinogens for 5-HT₂ receptors in vitro and hallucinogenic potency in humans.^3,52,98,126 The 5-HT_2A receptor subtype appears to have the highest density in the cerebral cortex and may represent the binding site for hallucinogens.⁸⁰ This is bolstered by an animal study that shows that a selective 5-HT_2A antagonist can inhibit the effects of LSD and a phenylethylamine, 2,5-dimethoxy-4-iodo-amphetamine (DOI). The response to high doses of LSD and DOI suggest that both lysergamides and phenylethylamines are partial agonists at cortical 5-HT_2A receptors.^51,80,104

Although most investigations have focused on the role of serotonin for drug-induced hallucinations, other neurotransmitters are also involved. Stimulation of 5-HT_2A receptors enhances release of glutamate in the cortical layer V pyramidal cells.^3,8 LSD and other lysergamides stimulate both D₁ and D₂ dopamine receptors.^7,50,134 In animal models, LSD and phenylethylamine hallucinogens modulate NMDA receptor–mediated effects and may have a protective effect against neurotoxicity secondary to PCP and ketamine.^8,43

Another theory that incorporates these other neurotransmitters involves the concept of “thalamic filtering.”⁴⁹ The thalamus receives input and output from the cortex and reticular activating system, and functions to filter relevant sensory input. This theory has been explored as an explanation for organic psychosis and the effects of hallucinogenic drugs. Multiple neurotransmitters, including dopamine, acetylcholine, GABA, and glutamate, exert their actions on the thalamus. Increased excitatory or decreased inhibitory neurotransmitter in this region of the brain may lead to “sensory overload,” which manifests itself clinically as symptoms of psychosis.⁴⁹ Experimental evidence also demonstrates EEG abnormalities after administration of hallucinogens, confirming a cortical, rather the ophthalmologic, etiology for hallucinations.⁴²

Salvinorin A, the psychoactive component of Salvia divinorum, is one of the most potent natural hallucinogens. The effect of Salvinorin A occurs via binding at the κ-opioid receptor, making it structurally and mechanistically unique (Fig. 82–4).¹³⁸ The κ-opioid receptor is distinct from the µ opioid receptor, a stimulation that generally causes euphoria and analgesia (Chap. 38). Salvinorin A does not demonstrate any known serotonergic activity.¹³⁸

The opioid effects of Kratom have been attributed to mitragynine.^111,137 The most prevalent of the Kratom alkaloids, mitragynine shares a structural similarity with yohimbine.¹⁰ In vitro, mitragynine is active at both supraspinal opioid δ- and μ-receptors.¹²⁵ This μ-receptor activity results in analgesia and efficacy in treating opioid withdrawal symptoms. Additionally, mitragynine activates noradrenergic and serotonergic pathways.⁸³ Another Kratom alkaloid, 7-hydroxymitragynine, also demonstrates antinociceptive effects and high affinity for opioid receptors.⁸⁴ In animal studies, 7-hydroxymitragynine has more analgesic potency than morphine, even after oral administration.⁸²

Nutmeg contains a number of purportedly psychoactive compounds, including myristicin, elemicin, and safrole (Fig. 82–5). The psychoactive components of nutmeg include terpenes and alkyl benzyl derivatives (myristicin, elemicin, and safrole).⁹⁹

It is theorized that the aromatics found in nutmeg are metabolized to amphetaminelike compounds that create hallucinogenic effects.⁹⁹ However, this mechanism is unsupported by both theory and animal data.¹⁰⁵ Nutmeg contains myristicin and elemicin, both weak monoamine oxidase inhibitors that also demonstrate serotonergic activity, which may account for the clinical effects of nutmeg.¹⁰⁵

The pharmacology of atropine, a competitive central and peripheral antimuscarinic, and the most well studied belladonna alkaloid, is discussed in detail in Antidotes in Depth: A32. Like atropine, scopolamine and hyoscyamine are tertiary amines, which can cross the blood–brain barrier. Scopolamine causes more sedation than atropine, and its transdermal availability has led to its use in motion sickness patches. Hyoscyamine is more potent than atropine; it has traditionally been used as an antispasmodic for gastrointestinal conditions.

Physiologic changes accompany and often precede the perceptual changes induced by lysergamides, tryptamines, and phenylethylamines. The physical effects may be caused by direct drug effect or by a response to the disturbing or enjoyable hallucinogenic experience. Sympathetic effects mediated by the locus coeruleus include mydriasis, tachycardia, hypertension, tachypnea, hyperthermia, and diaphoresis. They may occur shortly after ingestion and often precede the hallucinogenic effects. Other clinical findings that are reported include piloerection, dizziness, hyperactivity, muscle weakness, ataxia, altered mental status, coma, and rhythmic, pupillary dilation, and constriction.⁷² Nausea and vomiting often precede the psychedelic effects produced by psilocybin and mescaline. Potentially life-threatening complications, such as hyperthermia, coma, respiratory arrest, hypertension, tachycardia, and coagulopathy, were described in a report of eight patients with a massive LSD overdose.⁶⁸ Sympathomimetic effects are generally less prominent in LSD toxicity than in phenylethylamine toxicity. Similar sympathetic symptoms are described after the use of 2C-B and 2C-T-7. Low doses of 2C-B and 2C-T-7 may produce hypertension, tachycardia, and visual hallucinations, while elevated doses are associated with shifts in color perception, enhanced auditory, and visual stimulation. Three deaths are associated with 2C-T-7 use; in one case, death may have resulted from seizures or aspiration.^34,39 An analog of 2C-B, called 2C-B-FLY, or Bromo-dragonFLY, is implicated in finger necrosis that requires amputation secondary to potent peripheral vasospastic activity as well as sudden cardiac death.⁹⁶ Similar vasoconstrictive effects resulting in limb ischemia may be induced by exposure to ergot containing alkaloids.

The psychological effects of hallucinogens seem to represent a complex and elusive interaction between different neurotransmitters, including the serotonergic and dopaminergic systems. Based on this serotonergic mechanism, serotonin toxicity could theoretically occur after the use of any of the lysergamide, indolealkylamine or phenylethylamine hallucinogens. Animal studies have documented LSD and tryptamine-induced serotonin toxicity.^117,132 Case reports have linked phenylethylamine use to fatal serotonin toxicity in recreational users.^92,133

Tolerance to the psychological effects of LSD occurs within 2 to 3 days with daily dosing, but rapidly dissipates if the drug is withheld for two days. Psychological cross-tolerance among mescaline, psilocybin, and LSD is reported in humans.¹⁴ There is no evidence for physiologic tolerance, physiologic dependence, or a withdrawal syndrome with LSD. Limited cross-tolerance is demonstrated between psilocybin and cannabinoids such as marijuana.²²

Salvia divinorum use results in vivid hallucinations and synesthesia.¹¹⁶ Additionally, its use may cause diuresis, nausea, and dysphoria. These aversive effects may limit its long-term recurrent use.¹⁰

The dual stimulant and sedative properties of Kratom contributed to its traditional use among manual laborers. However, its opioidlike activity has led to a surge in contemporary use as an herbal treatment for opioid withdrawal among patients with chronic pain.^18,19 Anorexia, weight loss, and insomnia are reported among Kratom addicts. Hyperpigmentation of the cheeks is also described among chronic users.¹²³

Recreational nutmeg use results in the desired effects of euphoria and hallucinations, as well as the adverse effects of nausea, vomiting, dizziness, flushing, tachycardia, and hypotension. Two case reports of fatalities from nutmeg ingestion are reported; however, it is unclear if these deaths truly represent nutmeg toxicity.^29,119

The belladonna alkaloids produce classic signs of anticholinergic toxicity, including hyperthermia, tachycardia, mydriasis, flushing, anhidrosis, urinary retention, and ileus. The central effects can include restlessness, hallucinations, agitation, delirium, seizures, and coma.³¹ The psychosis produced by belladonna alkaloids can be profound; in one case, a young man autoamputated his tongue and penis after ingestion of tea made from Angel’s trumpet.⁸¹

The vast majority of morbidity from hallucinogen use stems from trauma. Hallucinogen users frequently report lacerations and bruises sustained during their “high.” Additionally, dysphoria may drive patients to react to stimuli with unpredictable, and occasionally, aggressive behaviors. Many Internet sites regarding hallucinogen use advise readers to take hallucinogens only while under the supervision of a “sitter.”⁴⁰

The psychological effects of hallucinogens are dose related and affect changes in arousal, emotion, perception, thought process, and self-image. The response to the drug is related to the person’s mindset, emotions, or expectations at the time of exposure and can be altered by the group or setting.¹ The person experiencing the effects of a hallucinogen is usually fully alert, oriented, and aware that he or she is under the influence of a drug. Euphoria, dysphoria, and emotional lability may occur.

Illusions are common, typically involving distortion of body image and alteration in visual perceptions. Hallucinogen users may display acute attention to details with excessive attachment of meaning to ordinary objects and events. Usual thoughts seem novel and profound. Many people report an intensification of their sensory perceptions such as sound magnification and distortion. Colors often seem brighter with halolike lights around objects. Frequently, hallucinogen users relate a sense of depersonalization and separation from the environment, commonly called an “out-of-body” experience. Synesthesias, or sensory misperceptions, such as “hearing ­colors,” or “seeing sounds” are commonly described. Hallucinations may be visual, auditory, tactile, or olfactory.

Acute adverse psychiatric effects of hallucinogens include panic reactions, psychosis, and major depressive dysphoric reactions. Acute panic reactions, the most common adverse effect, present with frightening illusions, tremendous anxiety, apprehension, and a terrifying sense of loss of self-control.⁴⁶ These psychiatric effects may cause patients to seek care in the emergency department.

Routine urine drug-of-abuse immunoassay screens do not detect LSD or other hallucinogens. Although LSD can be detected by radioimmunoassay of the urine, confirmation by high-performance liquid chromatography (HPLC) or gas chromatography is necessary. These tests are rarely used in the clinical setting but are commonly available for forensic purposes.^14,37 False-positive urine immunoassay testing for LSD is reported after exposure to several medications, including fentanyl, sertraline, haloperidol, or verapamil.^47,102

Depending on their structure, phenylethylamines may cause positive qualitative urine testing by immunoassay for amphetamines. However, amphetamine drug screening is associated with numerous false positive results, particularly after the use of cold medications that contain ephedrine, pseudoephedrine, or phenylpropanolamine.¹²¹ Urine immunoassays do not detect 5-Meo-DiPT, DMT, AMT, 2C-T-7, and 2CB, but gas chromatography/mass spectrometry (GC/MS) testing methods for detection of these compounds has been described.¹³⁷

Routine urine drug immunoassay screens do not detect Salvinorin A, mitragynine, or myrsiticin. HPLC and liquid chromatography/mass spectrometry (LC/MS) protocols have been applied to the quantitative analysis of Salvinorin A and B in plant matter and in ex vivo animal studies. GC/MS identified Salvinorin A in urine and saliva obtained after two human volunteers smoked S. divinorum.⁹⁷ Myristicin testing is not widely available, but it can be obtained.¹¹⁹

Most hallucinogen users rarely seek medical attention because they experience only the desired effect of the drug. For any hallucinogen user who does present to the emergency department, initial treatment must begin with attention to airway, breathing, circulation, level of consciousness, and abnormal vital signs. Even in those in whom exposure to a hallucinogen is suspected, the basic approach for altered mental status should include dextrose, naloxone, and oxygen therapy as indicated, as is the vigorous search for other etiologies. Hallucinogens rarely produce life-threatening toxicity. Due to their rapid absorption, gastrointestinal decontamination with activated charcoal is of little value after clinical symptoms appear, and attempts may lead to further agitation. Sedation with benzodiazepines is usually sufficient to treat hypertension, tachycardia, and hyperthermia. The patient with a dysphoric reaction can be placed in a quiet location with minimal stimuli. A nonjudgmental advocate should attempt to reduce patient anxiety, provide reality testing, and remind the individual that a drug was ingested and the effect will wear off in a couple of hours. Physical restraint (without chemical restraint) should be avoided to prevent hyperthermia and rhabdomyolysis. Benzodiazepines remain the cornerstone of therapy for both autonomic instability and dysphoria, as the sedating effect can diminish both endogenous and exogenous sympathetic effects.⁸⁸ Autonomic instability and hyperthermia may be a feature of phenylethylamine use as well as tryptamine use or massive LSD overdose.^46,68,88 Hyperthermia resulting from agitation or muscle rigidity requires urgent sedation with benzodiazepines and rapid cooling. While central nervous system depression is unlikely to be severe enough to require endotracheal intubation in a patient with a pure hallucinogen exposure, intubation and paralysis may be required in the patient with intractable hyperthermia.¹⁶ Seizures may occur with tryptamine or phenylethylamine use and can be initially treated with benzodiazepines. Seizures may also result from hyponatremia in MDMA users and would necessitate treatment with 3% hypertonic saline (Chaps. 19 and 76).

The treatment of anticholinergic toxicity from the belladonna alkaloids involves several critical components: correction of abnormal vital signs, management of delirium, and rapid intervention for seizures or dysrhythmias. The mainstays of therapy are fluid resuscitation and benzodiazepines; however, physostigmine should be considered as antidotal therapy in cases of belladonna alkaloid poisoning. Conflicting data exist regarding the efficacy of physostigmine in decreasing morbidity and length of hospital stay when compared with benzodiazepines alone.^25,103 Based on the strength of evidence, physostigmine should be considered in patients with evidence of anticholinergic delirium or agitation if there are no contraindications. More information on physostigmine can be found in Antidotes in Depth: A9.

Morbidity and mortality typically result from the complications of hyperthermia, including rhabdomyolysis and myoglobinuric acute kidney injury, hepatic necrosis, and disseminated intravascular coagulopathy. However, for the most part, hydration, sedation, a quiet environment, and meticulous supportive care will prove adequate to prevent morbidity or mortality in recreational use or overdose.²⁸ Treatment of serotonin toxicity from phenylethylamine use is largely supportive and includes the avoidance of further administration of serotonergic medications. Specific therapy with agents like cyproheptadine may be warranted¹⁷ (Chap. 75).

The role of antipsychotics in controlling hallucinogen-induced agitation is unclear. Haloperidol, risperidone, and ziprasidone may have utility in controlling the acutely agitated patient. However, haloperidol and risperidone may worsen panic and visual symptoms, increasing the incidence of hallucinogen persisting perception disorder (HPPD; see below).² The safety of ziprasidone in hallucinogen users has not yet been reported. While further study on these agents is required, prolonged psychosis may require treatment with long-term antipsychotic therapy.

Long-term consequences of LSD use include prolonged psychotic reactions, severe depression, and exacerbation of preexisting psychiatric illness.^60,106 When LSD was initially popularized, some patients were noted to behave in a manner similar to schizophrenia and required admission to psychiatric facilities. In volunteer studies, panic reactions, HPPD, and extended psychoses were noted. When the drug was used for alleviation of anxiety and personality abnormalities, flashbacks and extended psychosis were reported.⁴⁵ It is suggested that these individuals had preexisting compensated psychological disturbances.^3,79

Flashbacks are reported in up to 15% to 80% of LSD users.⁵ Anesthesia, alcohol intake, and medication use may precipitate flashbacks.⁴⁸ These perceptions can be triggered during times of stress, illness, and exercise, and are often a virtual recurrence of the initial hallucinations. HPPD is a chronic disorder where flashbacks lead to impairment in social or occupational function. According to the Diagnostic and Statistical Manual V, the diagnosis of HPPD requires the recurrence of perceptual symptoms that were experienced while intoxicated with the hallucinogen that causes functional impairment and is not due to a medical condition.⁶ The etiology of HPPD is still unknown, and the reported incidence varies widely. Symptoms are primarily visual, and reality testing is typically intact in HPPD. Common perceptual and visual disturbances in HPPD include geometric forms, false and fleeting perceptions in the peripheral fields, flashes of color, intensified color, and halos around objects.⁷⁹ One finding described after LSD use is palinopsia, or “trailing,” which refers to the continued visual perception of an object after it has left the field of vision. These visual perceptions are associated with normal ophthalmologic examinations and abnormal EEG evaluations, suggesting a cortical etiology for the visual symptoms.

• Hallucinogens are a diverse group of drugs that alter and distort ­perception, thought, and mood without clouding the sensorium.

• The lysergamide, phenylethylamine, and tryptamine hallucinogens share a serotonergic mechanism of action; however, other neurotransmitters may be responsible for the complex effects of these hallucinogens.

• Acute adverse psychiatric effects of hallucinogens include panic reactions, true hallucinations, psychosis, and major depressive dysphoric reactions.

• Hallucinogens rarely produce life-threatening problems, but can cause autonomic instability, seizures, and hyperthermia, particularly in large ­overdose.

• Meticulous supportive care with attention to abnormal vital signs and sedation with a benzodiazepine is often the only therapy required.

Acknowledgments

Cynthia K. Aaron, MD, Jeffrey R. Tucker, MD, and Robert F. Ferm, MD, contributed to this chapter in previous editions.

References