The term "hallucinogen" is derived from the Latin alucinari, meaning to wander in mind or talk idly [1]. Hallucinogens are agents that alter perceptions without major autonomic or metabolic changes or agents that cause alterations in perception, cognition, and mood as their primary psychobiologic action in the presence of an otherwise clear sensorium [2]. A typical hallucination induced by a classical hallucinogen (i.e., mescaline, peyote) is more accurately described as a modification of regular perception, with the user usually aware of the illusory and personal nature of their perceptions [1]. In 1956, the psychiatrist Humphrey Osmond coined the term "psychedelic," meaning "mind-manifesting," to describe drugs such as lysergic acid diethylamide (LSD) and mescaline. The term is a reference to the drugs' ability to illuminate normally hidden aspects of the mind or psyche [3]. This term became popularized in the 1960s and is often used interchangeably with the term hallucinogen to describe both the classical hallucinogens and their effects.

Intense interest in hallucinogens in Western society began with the discovery of LSD. In 1938, in search of a new migraine medicine, Swiss biochemist Albert Hofmann synthesized LSD at the Sandoz Pharmaceutical laboratories. It was not until 1943, when some of the liquid chemical substance spilled onto his hand, that Hofmann experienced the first recorded LSD "trip." He recounted that 45 minutes after absorbing some of the chemical into his skin, he became increasingly dizzy, developed visual disturbances, and had a marked desire to laugh. An hour into the experience, he asked his assistant to call a doctor and accompany him home. In Hofmann's mind, he was not on the familiar street that led him home but instead on a street painted by Salvador Dali, a funhouse roller coaster where the buildings yawned and rippled [3].

Perhaps one of the most promising areas of investigation involving LSD was in the treatment of alcoholism. The initial rationale for LSD use in this context was the perceived similarity between the LSD effect and the experience of delirium tremens (DT) as described by patients with alcohol use disorder. It was hypothesized that LSD could safely replicate the DT experience, inducing fear and possibly benefiting patients with alcohol use disorder. Researchers revised their theoretical basis for using LSD for patients with alcohol use disorder when they realized that LSD had the potential to cause a surge of previously repressed material [50].

In 2019, an estimated 1,183,000 Americans older than 12 years of age tried a hallucinogen for the first time [54]. An annual national survey of drug use among high school students in the United States found that 6.9% of 12th graders reported lifetime hallucinogen use in 2019 and 4.6% reported hallucinogen use in the past year [8]. When specifically asked about LSD use, 5.6% reported lifetime use and 3.6% reported use in the past year. The percentages among 12th graders represent decreases compared to a peak in the late 1990s/early 2000s.

During 2019, approximately 6.0 million individuals 12 years of age or older used a hallucinogen on at least one occasion [54]. Among first-time hallucinogen users, an estimated 0.1% to 3% will become hallucinogen dependent [9,54,55]. In a study examining the characteristics of persons who become hallucinogen dependent, first use at an early age (10 to 11 years) was associated with increased risk, with the median elapsed time from onset of use to onset of dependence being 12 to 13 months [12]. These data validate previous reports of a very infrequent but tangible dependence syndrome developing soon after the onset of hallucinogen use [12]. The risk of hallucinogen dependence is also believed to be low if the hallucinogen was the first drug used. The risk of hallucinogen dependence is highest for recent-onset users of mescaline, MDMA, and PCP, and lower for psilocybin.

The classical hallucinogens are divided into two main classes based on molecular structure: indole and catechol. The indole class, also referred to as the tryptamines, consists of alkaloids that act on serotonin. They are thus named because the basic structure of the neurotransmitter serotonin is referred to as an indole nucleus, which comprises the core structure of all of the drugs in this group. Indole hallucinogens include psilocybin, LSD, lysergic acid hydroxyethylamide (LSA), DMT, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) [1,5,13,58].

The catechol class, or the phenethylamines, constitutes the second group of classical hallucinogens. This group is made up of plant alkaloids, such as mescaline and nutmeg. The amphetamine analogs that are considered designer drugs, such as DOM, 3,4-methylenedioxyamphetamine (MDA), MDMA, 2,5-dimethoxy-4-ethylamphetamine (DOET), and 3,4,5-trimethoxyamphetamine (TMA), may also be categorized in this class. The amphetamine analogs are a large group of drugs, and due to substitution on the ring of the catechol nucleus, their effects more closely resemble mescaline than amphetamine. The catechol nucleus closely resembles the catecholamine neurotransmitters dopamine and norepinephrine, and catechol hallucinogens act on catecholamine neurotransmitter systems [5].

Hallucinogenic drugs are pharmacologically heterogeneous and diverse, produce dissimilar effects, and likely work through distinct mechanisms. However, the classical hallucinogens all share a common mechanism: 5-HT2A receptor binding as partial agonists [2,15,60]. Of the hundreds of plants known to possess hallucinogenic properties, the active agents of these botanicals fall into surprisingly few chemical classes, with the indole nucleus of serotonin common to the majority of these compounds [1].

At higher doses, the initial effect consists of sympathetic arousal 20 to 30 minutes following ingestion, manifested as dizziness, anxiety, increased pulse and blood pressure, dilated pupils, piloerection, hyperreflexia, and mild pyrexia. Following this, there is a period of increasingly intense perceptual distortion; hallucinations can occur in any sensory modality, the most common being visual and the least common auditory [17]. The perception of time passage is often distorted. Synesthesia, whereby two or more senses are blended, and delusions are unusual.

Mental functions are differentially affected by LSD. Memory is unaffected, although perception, orientation, concentration, and other measures of cognition may be impaired in a dose-dependent manner. Cross-tolerance has been demonstrated in humans between LSD, psilocybin, and mescaline but not between LSD and amphetamines or cannabis. There have been no documented toxic fatalities from LSD ingestion [1].

LSA is a tryptamine found in the seeds of Ipomoea violacea (morning glory) and Argyreia nervosa (Hawaiian baby woodrose). When ingested, the drug is psychoactive through 5-HT2A receptor agonism. Morning glory seeds were used in Aztec rituals in ancient Mexico, and their popularity increased in the 1960s, when the seeds were used as a substitute for LSD. Morning glory seeds are consumed orally, either pulverized or as an extract of the psychoactive alkaloids. Threshold effects are noted with the ingestion of 3–6 g, with dosages of 200 to 500 seeds producing intense hallucinations as well as intense nausea, vomiting, and abdominal pain. Morning glory seeds and plants are sold in most nurseries and botanic supply stores. However, commercial morning glory seed producers coat the seeds with emetic agents in an attempt to discourage recreational ingestion [14,19].

A dosage of 12–20 mg of psilocybin produces an altered state of consciousness characterized by stimulation of affect; enhanced ability for introspection; altered psychologic functioning; perceptual changes, including illusions, synesthesia, and affective activation; and alterations of thought and time sense. As with any hallucinogen, the potential exists for a panic or severely dysphoric reaction in the user, although less so than with LSD [20,51].

5-MeO-DMT, a naturally occurring hallucinogen, is closely related to DMT. One source of 5-MeO-DMT is the Sonoran Desert toad, Bufo alvarius, which secretes large amounts of the hallucinogen from its parotid glands. Although the venom of B. alvarius is known to be toxic when consumed orally, it can be safely smoked. To extract the venom, the toad is held against a flat surface while the parotid gland is massaged. The liquid venom is then collected, dried, and smoked. Based on reported experiences, a single deep inhalation of the vaporized venom is powerfully psychoactive within 15 seconds. Consistent with the known effects of 5-MeO-DMT, the drug effect has been described as intense and short-lived, characterized by auditory and visual hallucinations. The strongest effects dissipate after five minutes, but residual changes in perception persist longer than one hour. No toxic effects have been reported. A single B. alvarius toad yields 0.25–0.5 g of dried venom. As concentrations of 5-MeO-DMT in the venom may be as high as 15%, one toad can yield as much as 75 mg of the hallucinogen that, when smoked, is effective in humans at doses of 3–5 mg. Thus, a single toad can produce more than 15 doses of one of the most potent psychoactive drugs found in nature [21].

The 1- to 4-inch diameter top portion of the cactus, referred to as the peyote button, is the section of the plant with the highest mescaline concentration. The peyote button can be eaten fresh or dried, steeped, or ground into a powder. A typical dose is 6 to 12 buttons, with each button containing 45 mg of mescaline. Mescaline is well absorbed in the gastrointestinal tract and within one hour of ingestion induces nausea, vomiting, abdominal cramps, dizziness, sweating, restlessness, and palpitations. The second phase of the drug effect begins within one to 3 hours of ingestion and is characterized by visual imagery, altered perceptions, and psychologic insight. The psychoactive effects typically last 6 to 12 hours [14]. Peyote use is legal for the 300,000 members of the Native American Church for ceremonial or religious purposes or to promote physical and mental well-being. Only licensed representatives of the Native American Church may legally harvest peyote cactus [19].

Nutmeg is the kernel inside the fruit of the evergreen tree Myristica fragrans, indigenous to the Maluku Islands in Indonesia. Historically, nutmeg has been used medicinally for various afflictions, including gastrointestinal disorders, musculoskeletal problems, and psychiatric conditions, and has a long history of recreational use. Although nutmeg use often results in unpleasant side effects, it is preferred by some users in search of a legal and easily obtainable euphoric drug with hallucinogenic effects. The hallucinogenic properties of nutmeg are caused by alkyl benzene derivatives (myristicin, elemicin, and safrole) and terpenes. Although the exact psychoactive mechanism is unclear, myristicin and elemicin are believed to be metabolized to amphetamine-like compounds similar to 3-methoxy-4,5-methylenedioxyamphetamine (MMDA) and TMA. Ground nutmeg is ingested in 5–20 g doses, or approximately 2 tablespoons of powder. Most users develop nausea and vomiting within an hour, followed by central nervous system (CNS) intoxication and hallucinations for three to eight hours. Undesirable effects include blurred vision, dizziness, drowsiness, xerostomia, flushing, palpitations, paresthesias, numbness, hypotension, and tachycardia [14,22].

A. muscaria is usually dried and consumed orally. The drying/heating process decarboxylates the ibotenic acid into muscimol, thus reducing toxicity and increasing the psychoactive effect. All parts of the mushroom are psychoactive, although the portion just under the skin may be most potent. An average dose is 5–10 g, and 10–30 g of dried mushroom is considered a high dose. The drug effect peaks 1 to 2 hours after ingestion, with a duration of 5 to 10 hours [28].

"Fry" is the term used to describe PCP-laced cannabis cigarettes that are soaked in embalming fluid, with embalming fluid consisting of formaldehyde, methanol, and ethanol. In some cases, tobacco cigarettes are used. The primary effect of smoking these cigarettes is toxic psychosis, with other effects including hallucinations, delusions, panic, paranoia, increased sexual arousal, and loss of consciousness. Side effects associated with the inhalation of embalming fluid include disorganized thoughts, decreased attention span, psychomotor agitation, and sympathetic nervous system up-regulation. Patients who have smoked this drug typically manifest severe dysphoric effects upon emergency room admission. Exposure to embalming fluid can result in bronchitis, body tissue destruction, impaired coordination, inflammation, brain and lung damage, and sores in the throat, nose, and esophagus [36].

Hallucinogen persisting perception disorder (HPPD), or "flashbacks," are characterized by persistent perceptual abnormalities that mimic the effects of acute hallucinogen intoxication. These abnormalities are not attributable to another medical or psychiatric condition and persist for weeks or months after the last hallucinogen exposure [43]. In order for a diagnosis to be established, the perceptual symptoms must cause clinically significant distress.

Although all classical hallucinogens have the potential to induce an extremely frightening experience, LSD probably accounts for most of the "bad trips" that come to the attention of medical providers due to the intensity of its effects and its prevalence relative to the other hallucinogens. Acute LSD toxicity commonly presents to the emergency department as a severely dysphoric or panic reaction superimposed on the drug effect. Effective management begins with a careful history and an accurate description of the ingested substance. Adulteration is surprisingly uncommon; mistaken attribution is more common. LSD toxicity historically has been managed with neuroleptics. However, it is now recognized that the neuroleptics may intensify the experience. Benzodiazepines (e.g., diazepam 20 mg orally or alprazolam 1–2 mg intramuscularly) are widely regarded as rapid and effective treatment, with resolution of symptoms often occurring within 30 minutes [1]. Toxic reactions to the other classical hallucinogens should be managed in the same manner [14,16].

Long-term dissociative use suppresses the production of dopamine and norepinephrine, which can persist into abstinence, possibly leading to depression. Antidepressants with noradrenergic and dopaminergic specificity can counteract this suppressant effect. Patients with post-dissociate depression should be maintained on antidepressant therapy for at least three to nine months [16].