Acknowledgments
The authors greatly appreciate the editing assistance of medical student Sean Doherty of Cardiff University School of Medicine.
Historical Perspectives
Psychoactive substances derived from botanicals have been used ritualistically used for millennia. Developments during the second half of the 20th century in neuroscience and in synthetic organic chemistry recast natural and synthetic intoxicants into a new biological and clinical light. These chemicals, referred to improperly as “hallucinogens,” alter psychoneurobiological behavior in ways both subtle and overt. The term “hallucinogen” suggests the induction of hallucinations, a symptom of psychosis well-known within clinical psychiatry, but this is not the case with most hallucinogens and some closely related substances (i.e., entactogens such as 3,4-methylenedioxymethamphetamine), which do not induce major sensory alterations. The terms “psychotomimetics” (psychosis-mimicking) and “psychedelics” have also been used. Psychotomimetic appears only rarely in the scientific literature, since, much like with hallucinogen, these substances are not primarily psychotogenic, whether mimicking or otherwise, although hallucinogens can exacerbate or contribute to worsening the mental health of those vulnerable to a formal thought disorder. The term “psychedelic,” first offered by the psychiatrist Humphrey Osmond, may be the most commonly used lay term for hallucinogens, and it used to be an accepted alternate descriptor in the scientific literature.
Albert Hofmann first synthesized lysergic acid diethylamide in 1938 and accidentally ingested it in 1943. Publishing on these findings heralded much research in the 1950s, when hallucinogens became the focus of intense interest in psychiatric research and stimulated the discovery of the neurotransmitter systems and their functions in the brain.
More than 10,000 subjects received lysergic acid diethylamide (and other hallucinogens) in controlled research settings in studies published from 1951 to the late 1960s, resulting in more than 1000 clinical papers, dozens of books, and six international conferences on their use as aids in psychotherapy.
A number of substances have been categorized as hallucinogens or hallucinogen-like: (1) the classical hallucinogens (e.g., mescaline, psilocybin, lysergic acid diethylamide, and dimethyltryptamine), (2) the entactogenic phenethylamines (3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, and methylbenzodioxolylbutanamine), (3) the anticholinergic delirants (atropine, hyoscyamine, and scopolamine), and (4) dissociative anesthetics/miscellaneous (N 2 O, ketamine, phencyclidine, and salvinorin A). This chapter focuses on the more commonly used classical and entactogenic hallucinogens, but will mention the other substances where appropriate or necessary.
Epidemiology
The Substance Abuse and Mental Health Services Administration’s (SAMHSA’s) National Survey on Drug Use and Health estimated that among Americans 12 years of age or older in 2006, close to 4 million used hallucinogens that year, with 1.1 million trying one for the first time ever, and some 35.3 million Americans have tried one at least once in their lifetime. Of a total of 23.6 million persons classified with any substance abuse or dependence in 2006, 380,000 Americans 12 years of age or older were estimated to meet Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition (DSM-IV) criteria for hallucinogen abuse or dependence. SAMHSA’s Warning Network data estimated that 16,408 emergency room visits for the entire United States in 2005 involved a hallucinogen (not including phencyclidine: 7535), with 10,752 for the entactogen 3,4-methylenedioxymethamphetamine and fewer than 1900 for the classical hallucinogen lysergic acid diethylamide (of a total of 1.45 million drug-related visits).
Among high school students, the Monitoring the Future data have shown a continuous decline since the late 1990s in the lifetime, annual, and past-month use of hallucinogens. In 2006, 8.3% of 12th graders in the United States reported lifetime use of hallucinogens, a drop from 15.1% in 1997.
Taken together, these numbers indicate that the prevalence of hallucinogen use still is lower compared with other substances of abuse in the United States and is significantly lower in morbidity and mortality. The prevalence of the various hallucinogen-related disorders is not known.
Basic Pharmacology
Table 57.1 lists some of the more commonly known hallucinogens. As shown by the table, the various hallucinogens are wide-ranging in dosage and duration. In general, hallucinogens exert their effects by sympathomimetic actions on the central nervous system. This activation may be due to agonist properties on different neurotransmitter-modulated brain systems that are adrenergic, dopaminergic, and, perhaps most importantly, serotonergic. The brain contains approximately 40,000 serotonergic neurons, mainly located in the dorsal raphe nucleus of the mid-brain. This tiny population of neurons maintains a widely distributed network throughout the brain, which modulates nearly every kind of brain activity.
| Class | Chemical Name | Common or Street Name | Source | Dosage | Route | Duration of Action | Major Neurobiological Target | Notes |
|---|---|---|---|---|---|---|---|---|
| Indolealkylamines | Lysergic acid diethylamide | LSD, Acid, Blotter | Synthesis | 50–200 μg | By mouth | 8–14 h | 5-HT 2A partial agonist | Distributed on small squares of blotting paper, drops of liquid, gel-caps, small pills |
| Psilocybin | Magic mushrooms, Shrooms, | Psilocybe cubensis, Psilocybe azurescens, and many other subspecies, Synthesis | 10–50 mg, 1–5 g dried mushroom; quite variable | By mouth | 4–8 h | 5-HT 2A partial agonist | Psilocybin is converted in the body to psilocin, the actual active hallucinogen. Continued shamanic use in Mexico. Bruising of mushroom turns blue. | |
| Dimethyltryptamine | DMT, Yopo, Cohoba | Psychotria viridis, Anadenanthera peregrina, Mimosa hostilis, and many other natural sources, Synthesis | 5–40 mg | Smoked, inhaled snuff | 30–60 min | 5-HT 2A partial agonist | Continued Amazonian shamanic use | |
| Dimethyltryptamine + monoamine oxidase inhibitors (harmala beta-carbolines) | Ayahuasca, yaje, Hoasca, Daime, “vine of the soul” | Psychotria viridis (dimethyltryptamine) + Banisteropsis caapi (monoamine oxidase inhibitor) | Variable | By mouth | 2–4 h | 5-HT 2A partial agonist | Brewed as a tea; religious sacrament | |
| Ibogaine | Ibogaine | Tabernathe iboga | 200–300 mg | By mouth | 12+ h | Likely 5-HT 2A partial agonist | Religious sacrament; long-acting metabolites may contribute to purported anti-opiate withdrawal benefits. | |
| Phenyl-alkylamines | 3,4,5-trimethoxy-phenylethylamine | Mescaline, Peyote, San Pedro | Lophophora williamsii, Echinopsis panachoi , other cacti, Synthesis | 200–500 mg, 10–20 g or 5–10 dried peyote buttons, 1 kg fresh E. pachanoi | By mouth | 6–12 h | 5-HT 2A partial agonist | Religious sacrament |
| Entactogenic phenyl-alkylamine | 3,4-methylenedioxy-methamphetamine | MDMA, Ecstasy, X, XTC, Rolls, Molly | Synthesis | 80–150 mg | By mouth | 4–6 h | Serotonin release and depletion | Mildly hallucinogenic at high doses |
| 3,4-methylenedioxy-amphetamine | MDA, Love drug, Adam | Synthesis | 75–160 mg | By mouth | 4–8 h | Serotonin release and depletion | ||
| 4-bromo-2,5-dimethoxy-phenethylamine | 2C-B, Nexus | Synthesis | 5–30 mg | By mouth | 4–8 h | Unknown | ||
| 4-chloro-2,5-dimethoxy-amphetamine | DOC | Synthesis | 1–5 mg | By mouth | 4–8 h | Unknown | Has been found on blotting paper | |
| 4-methyl-2,5-dimethoxy-amphetamine | DOM, STP | Synthesis | 1–10 mg | By mouth | 14–20 h | Unknown | Higher doses used in the 1960s resulted in many ER visits then. | |
| Dissociative | Ketamine | Ketamine, Special K, Vitamin K, K hole, | Synthesis | 25–50 mg (intramuscularly), 50–100 mg (by mouth or snorted) | Intramuscularly, by mouth, snorted | 1–2 h (intramuscularly), 1–4 h (by mouth) | N -methyl- D -aspartate antagonist | Sub-anesthetic dose: lost sense of time, space, verbal skills, balance, drooling |
| Dextromethorphan | DXM, Robo, DM | Synthesis | 100–600 mg | By mouth | 4–8 h | N -methyl- D -aspartate antagonist | ||
| Phencyclidine | PCP, Angel dust | Synthesis | 3–10 mg | By mouth | 8–24 h | N -methyl- D -aspartate antagonist | ||
| Other | Salvinorin A | Salvia, Sally D, Diviner’s sage | Salvia divinorum | 250–750 mg (smoked), 2–10 g dried leaves (by mouth) | Smoked, by mouth | 30–60 min (smoked), 1–3 h (by mouth) | Kappa-opioid selective agonist | Atypical hallucinogen; no longer found in the wild |
| Scopolamine and atropine | Datura, Jimson weed, loco weed, Thorn apple, Angel’s trumpet, belladonna, deadly nightshade | Datura stramonium, Atropa belladonna, many related species | Highly variable | By mouth | 12–48 h | Competitive muscarinic acetylcholine antagonist | Plants of the Solanaceae family contain various ratios of scopolamine to atropine; blurred vision | |
| Muscimol (5-(aminomethyl)-3-isoxazolol) | Fly agaric, Amanita | Amanita muscaria, Amanita pantherine | 1–30 g dried mushrooms | By mouth | 5–10 h | Gamma-aminobutyric acid-A agonist glutamate | Shamanic use in eastern Siberia; over 600 species of agarics—easy to misidentify. Some are extremely poisonous, such as “death cap” A. phalloides; mushrooms also contain ibotenic acid—as it dries/ages, decarboxylation of ibotenic acid creates muscimol. |
Despite heterogeneity, most classical hallucinogens appear to exert pharmacologic action through agonist effects on 5-HT 2A /c receptors. Hallucinogens have high affinity for serotonin receptors, and genetic or pharmacologic inactivation of 5-HT 2A receptors blocks behavioral effects in preclinical models as well as subjective effects in humans. Rapid tolerance develops due to receptor downregulation, and repeated administration leads to markedly diminished effects within several days.
It remains unclear as to whether a specific pattern of alterations of brain functioning is involved in the psychoactive effects of hallucinogens. Neurometabolic studies to date point to activation of the frontal cortex, limbic/paralimbic structures, and the right hemisphere.
Entactogenic substances, such as 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine, differ from classic hallucinogens by inducing a marked release of serotonin from serotonin-containing neurons and (to a lesser extent) dopamine release from dopamine-containing neurons. Their neurometabolic actions show minor deactivation of cortical regions and limbic activation as well as deactivation of the left amygdala. The latter may be responsible for their most prominent effect: the decrease of emotional tension and anxiety.
Psychological and Biological Effects
Intoxication with hallucinogens, commonly referred to as “tripping,” may induce some physiological effects that are quite subtle to observation and a wide variety of behavioral, emotional, and cognitive effects ( Table 57.2 ). The visual images experienced are usually not true hallucinations but rather illusions, such as the perception of geometric patterns or scenic dream-like visions appearing before closed eyes, perception of movement in stationary objects, and synesthesias. The content of visual and most emotional phenomena most often reflects the psychodynamics of the user. Colors may appear intensified, and humans (self and others) and animals may be viewed as altered or exaggerated directly or in mirrored reflection. Hallucinogens amplify affectivity and may cause significant changes of mood, with possible rapid changes from euphoria to depression or anxiety or vice versa. In extreme cases, especially with higher order overdoses, psychotic-like reactions may be experienced. In short, the psychological effects of hallucinogens are highly variable and strongly influenced by the individual’s psychological state at the time of ingestion (mind-set) as well as the social and physical setting.
| Intoxication may include a cluster of the following | |
|---|---|
| Physical Effects b | Psychological Effects |
Regular (mild to very mild):
|
|
a Indolealkylamine and phenylalkylamine hallucinogens only (see Table 57.1 )
b Some effects are reactionary to psychological content (e.g., increased heart rate and nausea due to anxiety), and complaints can be dependent on factors such as mindset, setting, dose, and supervision. Intoxicated individuals may also deny physical impairment and/or claim increased energy, sharpened mental acuity, and improved sensory perception
c A subject experiencing “pseudo-hallucinations” retains the capacity to recognize that these perceptions are transient and drug induced, as opposed to true hallucinations in which no such discernment from reality is possible
Toxicity of lysergic acid diethylamide, psilocybin, and other classical hallucinogens is very low. Overdosing leads to psychological complications to psychological crises or (rarely) psychotic symptoms. However, no case of lethal overdose is known, and there is no evidence of toxicity beyond the acute state of intoxication. A recent review of the harmful consequences of drugs of abuse found that the classical (and the most used, by far) hallucinogen lysergic acid diethylamide is near the bottom in a ranking of risk to users and society.
Hallucinogen Use Disorders
Hallucinogen abuse and hallucinogen dependence are organized in the DSM-IV much like most other listed substance use disorders. Both are characterized by patterns of compulsive and repeated drug use despite the knowledge of significant harm caused by this use. Hallucinogen use only almost never leads to the development of classic dependence syndromes as seen with opiates or alcohol. By far the most typical pattern is for users to experiment with a few doses of a hallucinogen and then discontinue further use. Users do not experience withdrawal symptoms as seen with other substances of abuse, so this symptom is not a criterion in diagnosing hallucinogen dependence. Note that tolerance rapidly increases, in general, when hallucinogens are used with frequency, which strongly limits their use on a regular basis.
Hallucinogen-Induced Disorders
The DSM-IV allows for the diagnosis of numerous substance-induced disorders. Specific to hallucinogens are hallucinogen intoxication, hallucinogen persisting perception disorder, and hallucinogen-induced psychotic, mood, anxiety, delirium, or “not otherwise specified” disorder. These disorders arise in the context of substance use and may manifest during intoxication, during withdrawal, or long after the drug has been ingested and the acute effects have subsided. The diagnosis of a hallucinogen-induced psychotic, mood, anxiety, or delirium disorder is made only if the symptoms are in excess of what is expected from intoxication or withdrawal.
Assessment and Treatment
Hallucinogen Intoxication
The Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision (DSM-IV-TR) criteria for hallucinogen intoxication are presented in Table 57.3 .
