Volume 61, Issue S2 p. S100-S113
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Pharmacologic Similarities and Differences Among Hallucinogens

Kristin Waters PharmD, BCPS, BCPP

Corresponding Author

Kristin Waters PharmD, BCPS, BCPP

School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA

Corresponding Author:

Kristin Waters, PharmD, BCPS, BCPP, University of Connecticut, School of Pharmacy, 69 North Eagleville Rd, Storrs, CT 06269

Email: [email protected]

Search for more papers by this author
First published: 15 August 2021
Citations: 4

Abstract

Hallucinogens constitute a unique class of substances that cause changes in the user's thoughts, perceptions, and mood through various mechanisms of action. Although the serotonergic hallucinogens such as lysergic acid diethylamide, psilocybin, and N,N-dimethyltryptamine have been termed the classical hallucinogens, many hallucinogens elicit their actions through other mechanisms such as N-methyl-D-aspartate receptor antagonism, opioid receptor agonism, or inhibition of the reuptake of monoamines including serotonin, norepinephrine, and dopamine. The aim of this article is to compare the pharmacologic similarities and differences among substances within the hallucinogen class and their impact on physical and psychiatric effects. Potential toxicities, including life-threatening and long-term effects, will be reviewed.

Hallucinogens, also known as psychedelics (“mind-revealing”) or psychomimetics (“psychosis-mimicking”), are classified for their ability to alter thought, perception, and mood at nontoxic levels.1-4 These agents are generally considered nonaddictive.1, 2 The broad description of what constitutes a hallucinogen lacks specificity; cannabis, for example, may produce similar or overlapping effects through different mechanisms but is not considered a hallucinogen.2 It has been suggested that a more accurate description of hallucinogens would include substances with a primary site of action at the serotonin 5-HT2A receptor.2, 5 However, not all hallucinogens meet this definition as some do not have known serotonergic effects. Lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT) have been dubbed classical hallucinogens, although several other hallucinogens exist and will be discussed in this article (see Table 1 for street names).3

Common psychological effects of hallucinogens include perceptual effects (changes to sense of time and space), depersonalization, distortions, illusions (misinterpretation of a sensory stimulus), perceptual intensification, and hallucinations (auditory, visual, or sensory experiences that originate without external stimuli). An intensifying or altered sense of color, light, sound, and texture is often described.3-6 Other visual illusions include objects appearing larger (macropsia) or smaller (micropsia) than their actual sizes.6 The visual disturbances induced by hallucinogens are colloquially referred to as “trips.”7 Desired emotional effects of hallucinogens commonly include intensification of feelings, higher degree of consciousness, and euphoria that encompasses wonder and bliss. Negative emotional effects such as fear, paranoia, or a loss of control are also possible with the final emotional state influenced by the external environment.3 For many hallucinogens, the distinction between a toxic and nontoxic ingestion cannot be determined based on blood levels, as the mind-altering effects that may be considered toxic are often the very effect that the user is hoping to experience.

Acute psychotic effects are possible with all hallucinogens to be discussed. Although uncommon, there are reports of prolonged psychosis following hallucinogen use.8-10 Some people who use hallucinogens experience flashbacks of various aspects of the previous “trip” for days to weeks after the initial ingestion. These flashbacks can range from pleasant to terrifying visual illusions.7, 10

The estimated 12-month prevalence of hallucinogen use is 0.62% to 2% in the United States but because phencyclidine is the only hallucinogen included on standard toxicologic screens, the true incidence of use is not known.8, 11, 12 Although it is estimated that hallucinogens are used less commonly than stimulants or cannabinoids, additional hallucinogenic substances have recently become available, which may contribute to increased consumption in the future.13

Hallucinogens have been incorporated into cultural and religious practices for thousands of years. The Mazatec tribe in Oaxaca, Mexico, likely introduced Westerners to psychedelics such as magic mushrooms and ayahuasca while participating in shamanistic rituals in the early 1950s.14 Psychedelic drug use experienced a boom in the United States during the “hippie movement” of the 1960s and 1970s in response to the Vietnam War. Psychedelic drugs were believed to provide a path to spiritual enlightenment and served to oppose mainstream culture.15 The passage of the Controlled Substances Act in 1970 created harsh penalties for possession and use of many hallucinogenic drugs. This act, along with the end of US participation in the Vietnam War in 1973, significantly diminished hallucinogen use.16

Most hallucinogens are currently classified as Schedule I by the US Drug Enforcement Agency, meaning that they have high potential for abuse, no currently accepted medical treatment use, and a lack of accepted safety for use under medical supervision. However, there has been renewed interest in the potential therapeutic effects of hallucinogenic compounds in recent years. Clinical trials have been conducted in humans to assess the potential benefits of hallucinogens for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), major depressive disorder, anxiety disorders, substance use disorders, obsessive-compulsive disorder, and suicidal ideation.17-20 Some studies have reported clinically significant treatment outcomes, although current evidence is derived from highly heterogeneous trials.

This article will focus on describing the pharmacology and associated effects of individual hallucinogenic agents, comparing similarities, and differences in this class, and describing toxic effects and available treatments.

Serotonin 2A Receptor Agonists

The classical hallucinogens elicit their hallucinogenic effects through agonism of the serotonin 5HT2A receptor. In contrast, 5HT1A receptor affinity has not demonstrated the same psychoactivity, and not all 5-HT2A agonists activity have hallucinogenic properties.21 One hypothesis is that the stimulation of 5-HT2A receptors in certain regions of the brain is associated with an increase in spontaneous glutamate-mediated synaptic activity.22 It has been demonstrated that the effects of serotonergic hallucinogens can be blocked by administration of 5-HT2 receptor antagonists such as ketanserin and pirenperone.22-24 Substances with higher affinity for the 5-HT2 receptors have a higher psychoactive and hallucinogenic potency in humans. One study in zebrafish demonstrated that increased potency at the 5-HT2A receptors may correlate with a higher abuse potential by comparing the behavioral effects following administration of placebo, 3,4-methylenedioxymethamphetamine (MDMA), and 2 MDMA derivatives.25 The serotonergic hallucinogens can be further broken down into several subcategories: simple indolamine tryptamines, ergotamine tryptamines, and phenethylamines.2, 26

Simple Indolamine Tryptamines

The amino acid tryptophan can be broken down to form natural tryptamines including serotonin.26 Hallucinogenic tryptamines, including psilocybin and DMT, share an indole ring structure combined to an amine group by a 2-carbon side chain and have some structural similarities to the phenethylamines (see Table 2 for chemical structures).2, 26 These agents agonize several serotonergic receptors, including the 5HT2a and 5HT1a receptors; the simple tryptamines have a lower affinity for the 5HT2a receptors as compared to the hallucinogenic phenethylamines.26

Psilocybin

Psilocybin, the psychedelic component of “magic mushrooms” is a compound derived from several mushroom-forming fungi species including the potent Psilocybe genus.27, 28 Psilocybin is a prodrug and undergoes rapid dephosphorylation in the digestive tract and kidney to form its most prominent active metabolite, psilocin (4-hydroxy-N,N-dimethyltryptamine).2, 27, 28 Psilocybin has been ingested for centuries in sacred rituals in areas including South America, Mexico, India, Japan, and New Guinea.28 Psilocybin and psilocin were first identified in a laboratory setting in 1958 and were investigated in the 1960s and 1970s for their role in “understanding of etiopathogenesis of selective mental disorders” and as a psychotherapeutic.28 Psilocybin was also used recreationally during this time period, but with Schedule I classification in 1970, research was discontinued until the 1990s.28

Table 1. Commonly Used Street Names of Hallucinogenic Substances
Substance Commonly Used Street/Slang Namesa
Indolamines: Simple tryptamines
Psilosybin Magic Mushrooms, Shrooms, Mushrooms, Little Smoke, Purple Passion
DMT Businessman's Trip, Dimitri
Indolamines: Ergolamines
LSD Acid, Blotters, Blotter Acid, Dots, Mellow Yellow, Window Pane, Yellow Sunshine
Lysergic acid amide (LSA) Elephant Creeper, Wooly Morning Glory, Glories, Heavenly Blue, Pearly Gates, MG seeds, Flying Saucers
Phenalkylamines
Mescaline Buttons, Cactus, Mesc, Peyoto
Novel tryptamines
5-MeO-DMT 5-MEO, 5-Methoxy, Toad Venom
5-MeO-DIPT Foxy, Foxy-Methoxy
AMT Spirals
5-MeO-AMT Alpha-O, Alpha, O-DMS
4-OH-DiPT Moxy
4-OH-MET Colour, Metocin
Mixed serotonin and dopamine reuptake inhibitors and releasers
MDMA Molly, Ecstasy, Adam, Beans, Biscuit, Clarity, Disco Biscuit, E, Eve, Go, Hug Drug, Lover's Speed, Peace, STP, X, XTC
NMDA receptor antagonists
Phencyclidine Angel, Angel Dust, Hog, Ozone, Rocket Fuel, Shermans, Embalming Fluid, Purple Rain
Dextromethorphan Dex, Poor Man's PCP, Robo, Skittles, Triple C, Velvet
Atypical hallucinogens
Salvinorin A Magic Mint, Maria Pastora, Sally-D, Sheperdess’ Herb, Diviner's Sage
Datura stramonium Jimson Weed, Locoweed, Thorn Apple, Ditch Weed, Devil's Seed, Crazy Tea
Ibogaine Iboga
  • a Not all-inclusive.
Table 2. Chemical Structures of Hallucinogenic Substances
Hallucinogen Structure
Psilocybin
4-phosphoryloxy-N,N-dimethyltryptamine InlineGraphics
DMT
N,N-dimethyltryptamine InlineGraphics
Lysergic acid diethylamide (LSD) InlineGraphics
Lysergic acid amide (LSA) InlineGraphics
Mescaline
3,4,5-trimethoxyphenethylamine InlineGraphics
Novel hallucinogens
5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) InlineGraphics
5-methoxy-N,N-diisopropyltriptamine (5-MeO-DIPT) InlineGraphics
Alpha-methyltryptamine (AMT) InlineGraphics
5-Methoxy-alpha- methyltryptamine (5-MeO-AMT) InlineGraphics
4-hydroxy-N,N- diisopropyltryptamine (4-OH-DiPT) InlineGraphics
4-hydroxy-N-methyl- N-ethyltryptamine (4-OH-MET) InlineGraphics
MDMA
3,4-methylenedioxymethamphetamine InlineGraphics
Phencyclidine (PCP)
1-(1-phenylcyclohexyl) piperidine InlineGraphics
Dextromethorphan HBr InlineGraphics
Salvinorin A InlineGraphics
Datura Contains multiple distinct compounds
Ibogaine
10-methoxyibogamine InlineGraphics

Psilocybin can be ingested in the raw mushroom form or steeped in water to create a tea.2, 27 Following first-pass metabolism, the psychoactive psilocin is able to cross the blood-brain barrier. Psilocin strongly binds to many serotonin receptors, including 5HT1D, 5HT2A, 5HT2B, 5HT2C, 5HT5, 5HT6, and 5HT7.28 It also has activity at histamine-1, α2A, and α2B adrenergic receptors, and dopamine D3 receptors.29 Higher concentrations of serotonin remain in the synaptic cleft after use due to psilocin's ability to inhibit the sodium-dependent serotonin reuptake transporter (SERT).29

The typical hallucinogenic dose of psilocybin is ≈15 mg; however, the amount per mushroom can vary widely. The effects of psilocybin are highly dose dependent, with low doses being mildly sedating with “enhanced visual acuity” and high doses being more stimulating and producing more visual distortions.28 For most adults, 2 to 6 mushrooms is considered “sufficiently effective.”30 The effects typically begin 20 to 60 minutes following oral ingestion and last from 2 to 4 hours.28 Although psilocybin is known to produce effects similar to LSD, it is estimated to be ≈45 times less potent than LSD; higher doses are therefore required to achieve the same effect.2, 30, 31 Psilocybin is currently being studied in the treatment of mood disorders, although studies are limited. At this time, controlled trials that included subjects with mood disorders have demonstrated acute and long-term (6 months) improvement in mood and anxiety symptoms in patients with advanced-stage cancer.32-34

N,N-dimethyltryptamine

DMT is derived from the leaves of several plant species including Psychotria viridis, Desmanthus illinoensis, and Phalaris arundin acea.2, 35 Because DMT is rapidly deactivated by monoamine oxidase-A (MAO-A) in the liver and gut, it does not have psychedelic properties when consumed orally on its own. Ayahuasca, or “vine of the souls,” is a mixture containing DMT along with the Banisteriopsis caapi plant. This plant contains alkaloids that act as MAO-A inhibitors to prevent the rapid deactivation of DMT by the gut and liver.2 Ayahuasca has historically been consumed by indigenous people in South America.2 Ayahuasca tea contains ≈24 mg of DMT per 100 mL of liquid. Commonly reported doses of DMT range from 40 to 50 mg when smoked, although doses up to 100 mg have been documented.36 Dose-response studies in humans have shown that while lower doses of DMT produce mild stimulant effects, higher doses can cause more visual hallucinations.36, 37 The effects typically begin within 1 hour and last for ≈4 hours with oral ingestion. When smoked, DMT can be consumed on its own, as it bypasses the first-pass MAO-A effect in the gut and is readily bioavailable; the onset is within a few minutes but lasts for only 30 minutes, leading to its nickname: “the businessman's trip” (ie, during a lunch break).35

Ergotamine Tryptamines

The ergotamine tryptamines are named for their original source: the ergot fungus. This group is more complex in structure than the simple tryptamines, primarily due to the presence of an indole system (bicyclical combination of benzene and pyrrole ring) and tetracyclic ring, lending a structural similarity to serotonin.2, 26

Lysergic Acid Diethylamide

LSD is a highly potent serotonergic hallucinogen. It has a high affinity for 5HT1A, 5HT2A, and 5HT2C receptors along with D2 and α2 receptors. LSD was first synthesized in 1938 by the Swiss chemist Dr Albert Hofmann in the hopes of developing a circulatory and respiratory stimulant.38, 39 However, when the effects of LSD were noted to mimic the symptoms of schizophrenia, LSD was used to model psychosis.39 Before 1970, there was interest in using LSD to treat psychiatric and substance use disorders.38 Interestingly, LSD was also tested as a “psychochemical” for a potential role in unconventional warfare by the United States in the 1940s to 1950s.40 The Central Intelligence Agency also investigated the potential of using LSD as a “truth serum” during interrogations, including through a secret program known as MK-ULTRA which involved dosing of unknowing subjects.40, 41

The prevalence of LSD has remained relatively high in the United States since the 1970s compared with other hallucinogens. In 2010, 32 million Americans had reported lifetime use.42 A typical dose of LSD is from 50 to 200 μg, which may be ingested as an oral tablet, liquid, or on drug-soaked pieces of paper (blotter paper).38 In human trials, 75 μg administered intravenously significantly increased delusional thinking and disorganization, mimicking psychosis.31 While the psychological effects of LSD are similar to those of other hallucinogens, its high potency means that the blissful state, audiovisual synesthesia (blending of senses such as “seeing sounds” and “hearing colors”), derealization, and depersonalization may be significantly more intense.40

The maximum plasma concentration can be reached 1.5 hours after oral ingestion. LSD follows linear elimination kinetics and may take up to 12 hours for effects to dissipate. While the elimination half-life is ≈3 hours, the major metabolite (2-oxo-3-hydroxy-LSD) may remain active and be present in the urine for a longer period of time.43

Lysergic Acid Amide

Lysergic acid amide (LSA) is a naturally occurring alkaloid and analogue of LSD. Although they are structurally similar, differences in pharmacologic effects have been documented.44 LSA can be found in the seeds of plants from the Convolvulaceae plant family including Argyreia nervosa (Hawaiian baby woodrose) and Ipomoea violacea (morning glory). Argyreia nervosa has long been used as a medical plant in regions of India, while Ipomoea violacea and the related Ipomoea corymbosa were historically used for shamanic and ceremonial purposes in Central America. The Mazatecs continue to use the seeds of these plants.35 A study published in 2013 suggests that there may be a resurgence in use in the United States following its peak in the 1960s, potentially due to the low price, widespread availability, and lack of legal restrictions.45

The mechanism of action of LSA remains unclear; its binding profile has some similarities to that of LSD, but LSA has demonstrated a lower affinity for all receptors.44 Although LSA may produce similar changes in visual perception as elicited by LSD, the psychedelic effects are weaker, likely due to the significantly higher affinity of LSD for 5HT2 receptors.44, 45

The seeds of these plants may be ingested whole, ground up, suspended in beverages, or formulated into capsules.11, 46 A hallucinogenic dose of LSA ranges from 2 to 5 mg.35 This can generally be obtained from 5 to 10 seeds of Argyreia nervosa (0.14% LSA by dry weight) or 150 to 200 seeds of Ipomoea violacea (0.02% LSA by dry weight).35, 47-49 The onset of effects is rapid, and the effects typically last from 4 to 8 hours.35

Phenalkylamines

The serotonergic hallucinogens discussed thus far are known to bind relatively nonselectively to most 5-HT receptors. The phenylalkylamines are more selective and bind the orthosteric binding site of the 5-HT2 receptors including 5-HT2A, 5-HT2B, and 5-HT2C.29 Although the synthetic cathinones (“bath salts”) are derived from phenalkylamines and can sometimes cause sensory distortions, discussion of these substances is beyond the scope of this article.

Mescaline

Mescaline (3,4,5-trimethoxyphenethylamine) is a naturally occurring alkaloid that can be found within several Cactaceae species, including the North American peyote cactus (Lopophora williamsii) commonly known as “peyote” and the San Pedro cactus in South America (Echinopsis pachanoi).4 Mescaline makes up 0.4% of fresh peyote and 3% to 6% of dried peyote, with the highest concentration in the cactus buds. The peyote plant contains a variety of other phenylethylamine alkaloids, although mescaline is the primary psychedelic agent.4, 50 Peyote has been used for medicinal purposes for thousands of years, with documented use by North American indigenous people as long as 5700 years ago.4, 51 Peyote is classified as a Schedule I substance in the United States, although its use is currently protected for the Native American Church during religious ceremonies.4, 52

Mescaline's pharmacologic effects are 2000 and 20 times less intense than LSD and psilocybin, respectively.4, 53 It is a full agonist of the 5HT2C receptor, with some agonism of 5HT2A, 5HT2B, and 5HT1A receptors.4, 54 The phenylethylamine moiety of mescaline gives the agent some amphetamine-like dopaminergic activity.4 The dried peyote cactus buds or “buttons” may be consumed by mouth or used to prepare beverages such as tea. Mescaline can be smoked, insufflated, or formulated as a tablet.4 An average dose is from 20 to 500 mg, which is generally equivalent to 3 to 6 cactus buds or 10 to 20 g of dried peyote.4, 55 The onset of effect can be expected within 1 to 3 hours. Although less intense than other serotonergic hallucinogens, the effects of mescaline may last as long as 10 to 12 hours.55

Novel Tryptamines

Many serotonergic hallucinogens have been developed for recreational use in recent decades. This group of substances is sometimes referred to as the “designer drugs,” “entactogens,” or “legal highs,” with molecular structures based on those of existing illicit drugs.2, 26 Most substances in this category begin as structurally similar to the indolamine hallucinogens with modifications at position 4 or 5; a hydroxyl or methoxy group added at these locations can enhance the potency.2, 26, 54

This group of substances includes the substituted tryptamines 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-methoxy-N,N-diisopropyltriptamine (5-MeO-DIPT), alpha methylated tryptamines (5-MeO-AMT), and 4-substituted tryptamines (4-OH-DiPT, 4-OH-MET).21, 26 These substances have demonstrated full or partial nonselective agonist activity at the 5HT2A receptors in an in vitro study.21 4-OH-MET and 4-OH-DIPT also interact with the serotonin and norepinephrine transporters, similar to the mechanism of action of MDMA.21 The number of psychoactive products that have been introduced into the illicit drug supply has increased significantly in recent years. A complete review of these more recently introduced hallucinogenic substances is beyond the scope of this article but it is important to know that relevant pharmacokinetic and safety data are woefully lacking.

Mixed Serotonin and Dopamine Reuptake Inhibitors and Releasers

3,4-Methylenedioxymethamphetamine

MDMA is believed to be the most widely used designer drug in most countries and has held a place in rave (dance party) culture since the 1980s.26, 56 It contains a phenethylamine core structure but differs from previously discussed phenethylamines in that it binds to and inhibits SERT, dopamine, and norepinephrine transporters, with more potent action at SERT. This leads to increased levels of those monoamines in the brain by preventing their reuptake.56 MDMA is also a potent releaser of serotonin, dopamine, and norepinephrine and prevents their repackaging into vesicles for transport.56, 57 As a derivative of methamphetamine, amphetamine-like properties are evident.

MDMA produces fewer perceptual alterations than other hallucinogens, and is commonly termed an empathogen because of its ability to make the user feel close to others and bring out feelings of trust, openness, and empathy.58 It has strong mood-enhancing effects and may produce feelings of euphoria and anxiolysis. Some of the unique socioemotional effects of MDMA may be explained by its ability to induce the release of oxytocin, a neuropeptide that promotes social bonding and trust.59

MDMA was first synthesized in 1912 with the intention of creating a hemostatic drug. It was used by the US military in the 1950s in an attempt to identify “truth serums” during interrogation sessions.56 In the 1970s and 1980s, MDMA may have been used on thousands of patients to facilitate psychotherapy or for the treatment of anxiety, PTSD, and other psychiatric conditions.56 Due to concerns of abuse and the adverse effect profile, it was eventually classified as a Schedule I controlled substance in 1985. Clinical trials including MDMA resumed in 2011, with modern studies investigating its potential role in the treatment of major depressive disorder, PTSD, and autism spectrum disorder.17, 20, 56, 60

The average dose of MDMA is 75 to 150 mg, and it is usually consumed as an oral tablet or capsule. It can also be insufflated. It should be noted that pills marketed as MDMA also commonly contain other drugs such as methamphetamine.56, 57 The onset of action is ≈0.5 hour with a peak after 1.5 to 3 hours.18, 57 MDMA is rapidly absorbed in the gastrointestinal tract when consumed orally and is able to cross the blood-brain barrier.18 Its elimination half-life is ≈8 hours. Several enzymes, including cytochrome P450 (CYP) 2C19, CYP2B6, CYP2D6, and CYP1A2 are involved in the demethylation of MDMA and subsequent creation of several metabolites.56, 59, 60 Genetic polymorphisms may contribute to variations in pharmacokinetics of MDMA. For example, 1 human study demonstrated that CYP2D6 poor metabolizers experienced a higher concentration of MDMA, which correlated to higher blood pressure readings and more rapid subjective drug effects compared to CYP2D6 extensive metabolizers.61 Another human study also demonstrated that CYP2C19 metabolizers may have greater cardiovascular responses to MDMA compared to those without CYP2C19 variants.62 A degree of tolerance has been documented following repeated dosing of MDMA, which may be linked to the acute depletion of neurotransmitters; the pharmacologic effects, including euphoria, elicited by repeated dosing may be lower than what would be expected given the plasma concentration.63, 64 MDMA users who then redose to achieve the desired pharmacologic effects may experience more significant adverse effects, including suppressed mood.65

N-Methyl-D-Aspartate Receptor Antagonists

Dissociative hallucinogens enact their hallucinogenic effects by antagonizing N-methyl-D-aspartate (NMDA) receptors. Although phencyclidine and dextromethorphan are the focus of this article, other additional NMDA receptor antagonists are available. These include ketamine, a dissociative anesthetic that can also be used to treat depressive disorders, and the novel ketamine analogue methoxetamine.66 Other compounds, such as the PCP analogue tenocyclidine, are also available and have a high potential for misuse.

Phencyclidine

Phencyclidine (PCP; 1-(1-phenylcyclohexyl)piperidine) was developed in the 1950s and used as a dissociative anesthetic. However, due to its significant adverse effect profile including severe anxiety, dysphoria, and postoperative psychosis, PCP was removed from the market in 1965 and replaced in 1969 with ketamine, an analog of PCP with fewer adverse effects.67, 68

Recreational use of PCP became popular in the 1970s. Patients were being admitted to hospitals with all the core symptoms of schizophrenia, which were later attributed to PCP use. Early reports described it as a new “schizophrenomimetic” drug.69 PCP, a lipophilic arylcyclohexylamine, selectively binds and blocks neurotransmission at NMDA-type glutamate receptors as a noncompetitive antagonist.67, 69, 70 PCP additionally increases glutamatergic transmission at non-NMDA receptors and inhibits the reuptake of dopamine, serotonin, and norepinephrine while inhibiting output of GABA.67, 69, 71 Due to PCP's ability to so closely mimic the positive, negative, and cognitive symptoms of schizophrenia, its mechanism of action has been used to establish updated models of this disease, which implicate glutamatergic dysfunction as a contributor to the symptoms and cognitive dysfunction of schizophrenia.68, 70

Negative media statements about PCP in the 1970s, for example, that it was “the most dangerous drug in America” and a “devil drug,” contributed to its rescheduling from Schedule III to Schedule II in 1978.67 Sensationalized stories about its effects, including those of superhuman strength and extreme violence, likely led to the decreased prevalence of use in the United States during the 1980s and 1990s.67 Although precise patterns of use are not known, data suggest increasing use since the early 2000s. Emergency department visits due to PCP ingestion increased by 400% from 2005 to 2011.72

PCP is one of the least expensive illicit drugs to produce, and its synthesis is not complicated, although basic chemistry skills are required.67 PCP can be consumed via oral ingestion (on vegetable matter, pill or liquid form), inhaled, insufflated, or injected intravenously or subcutaneously. PCP can also be smoked after vegetable matter such as parsley, cannabis, or cigarettes are dipped in liquid PCP (known as “wet”).67, 68 The average dose differs according to formulation. An analgesic dose is considered to be 8 to 10 mg.67 A typical laced cigarette contains from 1 to 10 mg of PCP. A tablet may contain 1 to 6 mg. The standard inhaled dose is 10 mg, and for intravenous or subcutaneous, the dose can range from 0.1 to 0.25 mg/kg.67

The intravenous and intranasal formulations have the fastest onset, which can range from 30 seconds to 5 minutes. Oral ingestion has the slowest onset, at 15 to 60 minutes. The psychoactive effects of PCP generally last from 4 to 6 hours; however, there are documented cases of effects lasting from 48 hours up to several weeks. The elimination half-life is highly variable and can range from 7 to 57 hours (average of 17 hours).67 Because PCP is so highly penetrable into the brain and adipose tissue, it may be detected in brain and fat for up to 4 weeks after plasma drug levels are undetectable.67 Cases of prolonged psychosis following PCP intoxication have been documented, with the highest risk in chronic users. This psychosis may be difficult to treat with conventional antipsychotic medications.67, 73-75

Dextromethorphan hydrobromide

Dextromethorphan hydrobromide is an approved over-the-counter nonnarcotic antitussive in the United States and is included in many combination cold products. Also known as “poor man's PCP,” its ability to induce euphoric, hallucinogenic, and dissociative effects has led to its recreational misuse, termed robo-tripping.76 One study found that among adolescents, dextromethorphan was the most commonly misused legal medication contributing to emergency department visits.77

Dextromethorphan is extensively metabolized via first-pass metabolism through CYP2D6, while its major metabolite, dextrorphan, is metabolized by CYP3A4 and CYP3A5. Patients with CYP2D6 polymorphisms may experience a longer duration of action.78 Dextrorphan blocks NMDA receptors, which contributes to euphoria, dissociation, and agitation. It also binds serotonin receptors, σ-opioid receptors, and blocks the reuptake of adrenergic neurotransmitters.79 Although considered a dissociative hallucinogen, previous studies have shown that users often report similar subjective experiences following ingestion of dextromethorphan and psilocybin.80, 81 However, a more recent study showed that the subjective effects of psilocybin were greater than the effects of dextromethorphan in humans.82

A standard oral dose of immediate-release dextromethorphan is from 5 to 30 mg, although daily doses as high as 120 mg have been reported. Sixty milligrams is standard for extended-release formulations. Dissociation can occur within the 300- to 600-mg dose range, and at doses higher than 600 mg, the user may experience complete dissociation and coma.79 The onset of psychoactive effects generally occurs within 1 hour of ingestion.76

Atypical Hallucinogens

Salvinorin A

Salvinorin A, or salvia, is a dissociative intoxicant with hallucinogenic properties derived from the Salvia divinorum plant. Salvia is a potent, selective agonist of κ-opioid receptors with no action at serotonergic receptors.83 It has been used by the Mazatecs for centuries for medical and cultural purposes.84 Data from 2012 indicated that ≈2% of Americans had used salvia in the past month; 12% reported use within the past year with the highest rates of use in adolescent males.11 While not federally regulated, >30 states have enacted regulations on the sale or possession of salvia as of 2021. Most people who use salvia report sporadic use, with <20 lifetime uses.85 Subjective comparisons of salvia with other hallucinogens indicate that the effects are less focused on visual distortions compared with other substances and are less enjoyable.83, 85

The typical dose of salvia ranges from 200 to 500 μg. It can be ingested by chewing the fresh leaves of the mintlike plant, drinking a beverage with juice from the leaves, or smoking. The onset is rapid (5-10 minutes via the oral route and 1-2 minutes when smoked) and the effects are short-lived, lasting for an hour after oral ingestion and for ≈15 minutes when smoked.83

Datura

Datura is derived from the Datura stramonium plant and has been used for religious visionary and medicinal purposes since ancient times in areas including India and Europe.86, 87 Datura is highly anticholinergic, containing the major tropane alkaloids hyoscyamine and scopolamine along with some minor tropane alkaloids.86 These compounds competitively block acetylcholine at central and peripheral muscarinic receptors.87 Scopolamine is able to cross the blood-brain barrier to induce some of the effects of Datura including delirium, drowsiness, and agitation.87, 88 While the effects of Datura are sometimes compared to those of salvia, Datura is known to produce effects such as incoherent speech, psychosis, disorientation, delusions, delirium, and a “dreamlike frenzy.” Tactile hallucinations, such as crawling insects on the skin, are also common.

Datura is currently not controlled in the United States and is consumed mostly by adolescents and young adults. Because the effects of Datura are largely unpleasant, users commonly experience it as a 1-time experimentation. The effects of Datura can be variable and unpredictable.89 The highest number of alkaloids can be found in the leaves, seeds, and flowers of the plant; however, the number of alkaloids can vary even within different parts of the same plant.86,877 Datura has been implicated in accidental poisonings when the seeds or contaminated honey are mistakenly ingested. Datura can be ingested as a tea brewed from the leaves of the plant; it can also be consumed orally, smoked, or used topically.89 Common dosing is difficult to determine due to the variety of potentially active compounds and high variability in their dosages. Effects will generally occur within 30 to 60 minutes following ingestion and may be prolonged, especially in comparison with salvia. This prolonged intoxication may increase the likelihood that the user will present and require treatment at an emergency department.90, 91 Anticholinergic effects such as xerostomia, delirium, confusion, difficulty swallowing, and blurred vision are likely to occur first, followed by the psychoactive effects.92

Ibogaine

Ibogaine (10-methoxyibogamine) is 1 of ≈80 alkaloids derived from the Tabernanthe iboga plant. This plant has been used in West Africa as both a stimulant and a hallucinogen during religious rituals for at least hundreds of years.93, 94 First isolated in 1901, ibogaine was sold as an antidepressant and stimulant in France for 40 years.95 Ibogaine and its active metabolite, noribogaine, have been studied in both animal and human models as an antiaddictive agent.94-96 In rat studies, ibogaine has been shown to decrease self-administration of opioids (including morphine and heroin) and cocaine.94, 97 There is a paucity of studies in human subjects, but some observational studies have investigated ibogaine's role in the treatment of opioid use disorder although it is currently classified as a Schedule I substance.93, 95, 96

The mechanism by which ibogaine induces hallucinogenic effects is not completely understood. Ibogaine undergoes extensive first-pass hepatic metabolism, primarily through the CYP2D6 pathway, to form noribogaine.98, 99 Both ibogaine and noribogaine agonize μ-opioid receptors 5HT2, 5HT3, α2 and muscarinic acetylcholine receptors. Ibogaine is also a mixed agonist of κ1- and κ2-opioid receptors (similar to salvia but with less affinity) and antagonizes NMDA receptors, much like PCP and dextromethorphan.99, 100 Modulation of the μ-opioid receptors may be responsible for ibogaine's potential efficacy in treating opioid use disorder and opioid withdrawal.99 Ibogaine may also reduce the release of dopamine from the nucleus accumbens, which could diminish the pleasurable “rush” following opioid use.97, 101 Ibogaine is highly lipophilic; 1 animal study found that concentrations in the adipose and brain tissue in rats were 100 and 30 times higher than the plasma level 1 hour following subcutaneous or intraperitoneal administration, respectively.98 Although the half-life of ibogaine in humans is ≈7 hours, its behavioral effects may last ≥24 hours.96

Acute Toxicity

Acute complications of hallucinogen use may include injury as well as cardiovascular and central nervous system complications, metabolic disturbances, and hyperthermia. Patients have rarely been known to die from accidental traumas including drowning, motor vehicle accidents, homicide, and falls or jumps from great heights. Impaired cognition, including intense negative hallucinations, sometimes result in physical restraint by law enforcement or emergency medical providers, which has rarely been tied to fatalities even when the plasma concentration of the ingested substance was relatively low.38, 102, 103 These risks may be increased when multiple substances are ingested together.41, 104-110 Attempted and completed suicides have been documented.104-106, 110

Cardiovascular complications associated with hallucinogen use have resulted in fatalities. The release of endogenous catecholamines contributes to an intense sympathomimetic state with subsequent increases blood pressure, heart rate, and myocardial oxygen demand. As described above, the anticholinergic effects of some hallucinogens may also impact these parameters. This is especially dangerous for patients with underlying cardiovascular diseases like atherosclerosis/arteriosclerosis, heart failure, and arrhythmias. There have been cases of acute cardiac failure including Takotsubo cardiomyopathy, cardiac ischemia, and myocardial infarction in patients with preexisting cardiac conditions following the ingestion of psilocybin, 5-MeO-DIPT, MDMA, and ibogaine.111-114 Ibogaine has also been implicated in fatal cases of cardiomyopathy, QT prolongation, and ventricular arrhythmias, and cardiac hypertrophy, mostly in patients with preexisting cardiac issues, which has limited its use in the United States in the treatment of opioid use disorder.115, 116 Additional fatal cases of cardiotoxicity have been identified following the ingestion of MDMA in patients both with and without preexisting cardiac conditions. Chronic cardiac toxicity associated with hallucinogen use may include cardiomyopathy.117-119

Metabolic disturbances caused by hallucinogen ingestion include hyponatremia. While the precise mechanism is unknown, the hyponatremia is at least partly due to the enhanced release of antidiuretic hormone from the hypothalamus produced by serotonergic substances.120-122 Excessive water ingestion following hallucinogen use, especially with MDMA, may further worsen the hyponatremia.120, 121 This can progress to cerebral edema, which may have serious effects including seizures, coma, and death.120, 123

Hyperkalemia with rhabdomyolysis from extreme exertion (ie, use at dance/music festival scene) is another complication of hallucinogen use.120, 124 Hyperthermia may also be a complication of extreme agitation and psychomotor activity. Impaired sweating from an anticholinergic agent and inadequate fluid replacement may also contribute. Other complications of hyperthermia are disseminated intravascular coagulation and hepatic injury.125, 126

Serotonergic Toxicity

Serotonergic toxicity, including serotonin syndrome, is a possible complication following use of the serotonergic hallucinogens including dextromethorphan. Although exposure to a single serotonergic agent is rarely implicated, the risk of severe serotonin toxicity is higher when multiple serotonergic substances are ingested.120, 127 This is especially true if agents with different serotonergic mechanisms of action are involved (ie, those that block the reuptake of serotonin, those that increase the release of serotonin, and those that prevent the breakdown of serotonin).128 Serotonin syndrome may be life-threatening and is manifest by altered mental status, autonomic hyperactivity, and neuromuscular abnormalities such as hyperreflexia. LSD, MDMA, and 5-MeO-DIPT have a significant number of documented case reports of serotonin syndrome, some of which were fatal.129-131

Anticholinergic Toxicity

Severe, life-threatening anticholinergic toxicity may occur following Datura consumption. Anticholinergic poisoning can occur within 1 to 4 hours after ingestion. Psychiatric manifestations may include confusion, agitation, delirium, and hallucinations. Seizures, hyperthermia, hyperventilation, urinary retention, and arrhythmias are also possible.132 Common, less severe anticholinergic symptoms include constipation, dry skin, and mucous membranes, and mydriasis.133 While complete recovery is typical with supportive care, multiple fatal ingestions have been reported.88, 134 The acetylcholinesterase inhibitor physostigmine may be administered as an antidote.91, 92 Physostigmine has demonstrated the ability to reverse delirium and control agitation within ≈5 to 15 minutes in the majority of patients who present with anticholinergic toxicity and may shorten recovery time.92, 135 A recent trial randomized adolescent patients presenting with anticholinergic toxicity to receive either physostigmine or lorazepam; both treatment arms received a bolus followed by a 4-hour infusion of the drug.136 Although this was a small study (N = 19), physostigmine was superior to lorazepam at controlling the delirium and agitation associated with anticholinergic toxicity after both the initial bolus dose and following the 4-hour infusion. While there is no evidence to support the use of gastrointestinal decontamination, it is sometimes used for patients who have ingested a large quantity of Datura seeds.137

Cardiac Toxicity

Tachycardia and hypertension are common findings in patients presenting with acute hallucinogen toxicity. In addition to the fatal cases mentioned previously, rare, serious cardiovascular complications have been reported. In the context of severe intoxication with any hallucinogen, it is important that the patient is assessed for conduction disturbances and arrhythmias. Cases of cardiac arrest have been documented following use of DMT, psilocybin, LSD, and PCP.138, 139 As discussed, Datura consumption may lead to cardiac toxicity due to the high amount of atropine. Myocardial infarction has been identified following use of psilocybin, MDMA, Datura, and ibogaine.115, 117, 140 MDMA has also been implicated in cases of severe dilated cardiomyopathy and cardiac hypertrophy.117, 141, 142 The cardiac toxicity related to MDMA may be due to several mechanisms, including an increase in levels of synaptic monoamine neurotransmitters in the peripheral sympathetic system, activation of α-adrenergic, and serotonergic receptors, and an increase in central sympathetic responses.117, 143

In 1 case report, ibogaine produced a significant prolongation in the corrected QT interval to 616 milliseconds, which resulted in ventricular arrhythmias in a patient without previous cardiac history.144 Additional cases of corrected QT interval prolongation have since been published with ibogaine ingestion as well.115, 145, 146

Long-Term Effects

Long-term effects associated with hallucinogen use are not commonly reported but are possible. The serotonergic hallucinogens are considered to have low rates of dependence of ≈2% to 3% among current users but the estimated prevalence of MDMA dependence is mixed.147 One study noted that few people who use MDMA report intense cravings following exposure cues.148 However, another study of adolescent and young adults identified that 63% of those who reported repeated MDMA use indicated that they continued to use “despite knowledge of physical or psychological harm.”149 Chronic use of MDMA has been shown to reduce serotonin activity, including reduced SERT density in various brain regions although these changes may not be permanent.150

While PCP is generally not considered addictive because it does not typically produce strong cravings, chronic use does occur. There is evidence that chronic use may contribute to problems with memory, speech, and mood.95, 151 Persistent psychosis, hallucinations, delusions, and thought disorders that last for days to weeks are possible with chronic use compared to lasting hours with acute use. Cognition can become persistently impaired and cerebral blood flow may decrease.67, 152

A unique toxidrome that may be associated with chronic dextromethorphan hydrobromide use is bromide toxicity (bromism). Cases of patients presenting with, hyperchloremia (false elevation due to bromide's interference with ion-specific electrodes), facial acneiform eruptions, and psychiatric changes such as mood disturbance, perceptual distortions, and psychosis have been reported.153-156

Hallucinogen persisting perceptual disorder (HPPD) is a psychiatric condition defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, as “the re-experiencing, following cessation of use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen (eg, geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trails of images of moving objects, positive afterimages, halos around objects, macropsia, and micropsia).”157 Two subtypes of HPPD have been described: HPPD I (flashback type) and HPPD II.158 HPPD I is generally considered more benign and may include positive, short-term effects that are not distressing, although some patients may report feelings of annoyance.158 HPPD II is more severe and may include unpleasant, slowly reversible, or irreversible recurrences of the “trip” that can be disturbing and cause impairment in functioning. A case report of suicide following 10 years of HPPD following PCP or LSD exposure has been reported.159 Several treatment approaches for HPPD have been studied, with variable results. Treatments have included selective serotonin reuptake inhibitors, benzodiazepines, antipsychotics, clonidine, naltrexone, calcium channel blockers, β-blockers, and anticonvulsants.160

Conclusions

Many substances are able to elicit hallucinogenic responses, including both positive and negative mind- or mood-altering effects. These effects may include both acute complications of use as well as long-term psychiatric sequelae. This group of drugs is heterogeneous in terms of mechanisms of action, and newer, novel agents that skirt regulation continue to be introduced. Although the prevalence of hallucinogen use is poorly defined in the United States and is likely low compared to other more addictive substances, these substances do remain prominent in the drug use landscape. Diagnosis of patients presenting with complications of hallucinogen use is a challenge, as is the management of patients with more chronic substance use disorders.

Conflicts of Interest

The author declares no conflicts of interest.