Torsten Passie, MD, MA, and John H. Halpern, MD
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DEFINITION
Hallucinogen is the most widely accepted term for a group of chemically divergent substances primarily used for their potential to profoundly alter the processing of cognitive, perceptual, and emotional understanding of self and reality. Most hallucinogens produce visual alterations of perceived objects and pseudohallucinations, which are understood by the subject as not based in reality. The term “psychedelic” was coined to characterize substances capable of liberating perception from cultural conditioning, providing an opening to the transcendent qualities of being human, and potentially enabling humans to better understand themselves and their relationships with the world.
SUBSTANCES INCLUDED
A number of substances have been categorized as hallucinogens or hallucinogen-like: (1) the classical hallucinogens (e.g., mescaline, psilocybin, lysergic acid diethylamide or LSD, dimethyltryptamine or DMT), (2) the entactogenic phenylalkylamines (e.g., 3,4-methylenedioxyamphetamine [MDA], 3,4-methylenedioxymethamphetamine [MDMA], 3,4-methylenedioxyethamphetamine [MDE]), (3) the anticholinergic dissociatives (atropine, hyoscyamine, scopolamine), and (4) the dissociative anesthetics/miscellaneous (phencyclidine [PCP], ketamine, salvinorin A).
Classical hallucinogens possess an arylalkylamine skeleton of the indolealkylamine or phenylalkylamine type. Agents from this class do not necessarily produce identical effects. However, all bind at 5-HT2 serotonin receptors and, where known, all are 5-HT2a receptor agonists or partial agonists. Salvinorin A, derived from the plant Salvia divinorum, has clear-cut hallucinogenic effects but an unknown mechanism of action.
A somewhat separate and newer group of substances, which are often included in the category of hallucinogens, are the so-called entactogens (for their emotional and social effects) like MDMA and MDE. These usually do not induce major alteration in sensory perceptions, although they may be considered hallucinogenic in terms of significant alterations of conscious awareness of self and others.
METHODS OF USE AND ABUSE
More than 10,000 subjects received LSD (and other hallucinogens) from 1950 to the mid-1960s in controlled research settings for enhancing creativity, inducting “experimental psychoses,” educating psychiatric staff through temporary self-experience of quasi-psychotic states, and exploration of religious experiences. Currently, there is renewed interest in psilocybin and LSD as experimental tools for elucidating neural mechanisms of consciousness, the treatment of cluster headache, and in psychotherapy. A recent double-blind study of MDMA-assisted psychotherapy in PTSD patients showed significant success rates.
Nonmedical use and abuse of hallucinogens in Western culture started in the mid-1960s and were initially linked to the social turmoil of the 1960s’ student movement. Careless use often resulted in complications (e.g., physical accidents, brief psychotic reactions, and suicidality), which then established their new image as dangerous drugs. Overall rates of abuse and dependence are considered low compared to other substances.
Hallucinogen use very rarely leads to the development of physiologic dependence syndromes, such as seen with opiates or alcohol. As a class, the hallucinogens lack significant direct effect on the dopamine (DA)-mediated reward system; animals cannot be trained to self-administer these compounds. Users do not experience withdrawal symptoms, but tolerance rapidly increases when hallucinogens are used with frequency.
HISTORICAL FEATURES
Psychoactive substances derived from plant materials have been used ritualistically for millennia, often for religious and shamanic healing purposes. Ayahuasca remains an important spiritual medicine of many Native people of the Amazon Basin, and the peyote cactus, containing the hallucinogen mescaline, is the sacrament of the Native American Church (NAC) in the United States and Canada, with some 500,000 adherents.
One of the classical hallucinogens, LSD, was synthesized in 1938, and its psychoactive effects were accidentally discovered in 1943. After the discovery of its intense psychoactive effects in miniscule amounts, it became a force of intense interest in psychiatric research and stimulated the discovery of the neurotransmitter systems and their functions in the brain.
EPIDEMIOLOGY
The 2010 National Survey on Drug Use and Health estimated that almost 37.5 million Americans (14.8%) over age 12 ingested a hallucinogen at least once in their lifetime.
LSD is still the most widely used hallucinogenic drug; 23.3 million Americans used LSD at least once in their lifetime. Since the 1970s, there has been no decline in its use, especially in the United States and central Europe. Mescaline has never been synthesized and distributed for illicit purposes in the United States on a significant scale, and it is not mentioned in any drug abuse survey. The mescaline-containing peyote cactus is almost solely consumed in religious ceremonies of the NAC. DMT was never a significant drug of abuse beyond some tiny circles. The S. divinorum plant (containing the hallucinogen salvinorin A) is still legal in much of the United States with an estimated 1.8 million people having tried it.
PHARMACOKINETICS AND PHARMACODYNAMICS
In both its somatic and psychological effects, LSD is representative of most other hallucinogenic drugs. The pharmacology of LSD is complex, and its mechanisms of action are not completely understood.
Following oral administration, LSD is completely absorbed in the digestive tract. Psychological and sympathomimetic effects reach their peak after 1.5 to 2.5 hours at a plasma level of 6 to 7 ng/mL. The acute psychological effects of LSD last between 6 and 11 hours, depending on the dose. The half-life of LSD in humans is 175 minutes.
LSD-induced sympathetic stimulation is evidenced by pupillary dilation and slight increases in heart rate and blood pressure. Initial nausea, decreased appetite, temporary mild headache, dizziness, and inner trembling may occur. The most consistent neurologic effect is an exaggeration of the deep tendon reflexes and (more rarely) slight ataxia. No evidence was found for changes in liver and renal functions, blood cells, and electrolytes. LSD increases serum cortisol and growth hormone but does not alter serum prolactin levels.
Tolerance to autonomic and psychological effects of LSD occurs in humans after a few moderate daily doses, probably due to a reduction in receptor density. There have been no documented human deaths from an LSD overdose due to toxicity. The lethal dose of LSD in humans is estimated to be 1,400 mg, the equivalent of 14,000 recreational doses of 100 μg.
A moderate oral dose of LSD will significantly alter the state of consciousness, including stimulation of affect, enhanced capacity for introspection, and altered psychological functioning in the direction of hypnagogia and dreaming. Typical perceptual changes include illusions, pseudohallucinations, and synesthesias, as well as alterations of thinking and time experience. There is no evidence for long-lasting impairments in performance after LSD’s excretion.
Psilocybin
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are substituted hallucinogenic indolealkylamines. Because its metabolite psilocin is the psychoactive molecule, psilocybin is better referred to as a prodrug.
Psilocybin is readily absorbed following oral administration and is widely distributed throughout the body. Psilocybin and psilocin are detectable in plasma within 20 to 40 minutes, and full effects occur within 70 to 90 minutes and diminish over 3 to 4 hours. The half-life of psilocybin is approximately 160 minutes. The elimination of the glucuronidated metabolites as well as unaltered psilocybin (3% to 10%) occurs through the kidneys.
Neurovegetative effects include mydriasis, slight alterations in heart and breathing rate, and discrete hyperglycemic and hypertonic effects. Nausea and sleepiness can occur in the initial phase of intoxication. Electrolyte levels and liver enzyme activity are unaffected, as are endocrine cortisol, prolactin, and growth hormone levels. No serious toxicity with psilocybin has been reported in humans. The predicted human lethal dose of psilocybin is 14,000 mg (equivalent to approximately 4 kg of dried mushrooms). The psychopathologic phenomena induced by psilocybin are virtually identical to those of LSD.
Dimethyltryptamine
DMT is derived from various plant sources and animal venoms. DMT is also produced endogenously in humans in miniscule amounts. It is an endogenous sigma-1 receptor agonist.
DMT is quickly absorbed and distributed throughout the body and the brain. Maximal plasma levels of DMT are reached 2 minutes after intravenous (IV) administration and about 110 minutes after oral intake of ayahuasca. DMT is metabolized mainly by oxidative deamination and N-oxidation, catalyzed by monoamine oxidase. DMT and its metabolites are eliminated very quickly through the kidneys. Unusual for a hallucinogen, DMT does not induce tolerance in humans.
After smoking or via the IV route, initial effects occur in 30 to 60 seconds, peaking within 2 to 3 minutes, then clearing over the next 15 to 20 minutes. When ingested orally as the ayahuasca brew (i.e., DMT combined with an MAO inhibitor), effects commence after 30 to 60 minutes, peak within the first hour, and last for 3 to 4 hours. Ayahuasca is typically associated with nausea and vomiting, which may alter its absorption.
DMT significantly increases blood pressure and heart rate. These effects are significantly less when DMT is ingested as ayahuasca. DMT increases secretion of prolactin, growth hormone, ACTH, and cortisol, as well as corticotropin and β-endorphin. Overdoses of DMT may lead to seizure, but there are no lethal intoxications documented in the literature.
The psychological effects of DMT can be very frightening and may lead to injuries because of disorientation and motor incoordination. The psychological effects of DMT are milder with orally ingested ayahuasca (than with the pure drug) and are very similar to those of LSD and psilocybin.
Mescaline
The principal hallucinogenic compound of the peyote cactus is mescaline (β-3,4,5-trimethoxyphenethylamine). Mescaline is not a significant drug of abuse, and there are no serious physical complications or dependency syndromes known from peyote or mescaline. Evaluation of neurocognitive competence and psychological health of members of the NAC has shown them to perform as well as nonusing, healthy comparators.
Mescaline is absorbed rapidly and completely in the gastrointestinal tract. Onset of effects is typically 30 to 45 minutes. Peak intoxication occurs within 2 to 4 hours, wears off over the subsequent 4 to 6 hours, and correlates with plasma levels. Plasma levels of metabolites peak after 3 hours and then decline to virtually zero after 12 hours; 81.9% is eliminated unaltered in the urine 24 hours after oral ingestion and 26.2% as the phenyl acetic acid derivative.
Complete tolerance develops gradually within a few days and builds with repeated usage, lasting for a few days. No fatal intoxication from mescaline has been documented in the literature. The lethal human dose of mescaline is estimated to be 6,000 mg.
Mescaline is not as well researched with modern laboratory methods as the other classical hallucinogens. Like most hallucinogens, mescaline acts mainly on 5-HT2A receptors, but its somatic effects point to actions at adrenergic receptors. Somatic effects are strongest in the first 1 to 2 hours and then subside, replaced by the dream-like hallucinogenic state that lasts for 5 to 12 hours, depending on the dose. Secretion of prolactin and growth hormone occurs for a few hours, with peak increases at 90 to 120 minutes.
No serious somatic side effects or lethality have been reported from mescaline. There is no evidence of lasting cognitive or psychophysical effects with mescaline.
The typical mescaline intoxication is characterized by a dream-like state with enhanced alertness and affectivity; euphoric or dysphoric mood states; sensory–perceptual distortion; alterations of space and time sense; altered perception of color, sound, and shapes; complex hallucination; synesthesia; deconstructed perception; depersonalization; and ecstatic or mystical states of the mind.
Salvia divinorum and Salvinorin A
Salvinorin A is a neoclerodane diterpene alkaloid. It is structurally unrelated to any other hallucinogen and is found in the mint plant S. divinorum.
Salvia divinorum is most commonly inhaled by smoking the dried leaves or more concentrated leaf extracts. Other routes of administration include inhalation via volatilization or buccal absorption of tinctures. Users become less aware of their surroundings as dose increases, which can generate disorientation, incoordination, and dangerous behavior.
No explicit pharmacokinetic evaluations of S. divinorum have been completed. Salvinorin exerts its potent psychotropic actions through agonist action on the kappa opioid receptor. There is no evidence that it works on other receptor systems, but the endocannabinoid system may play a role. The psychological effects consist of mood changes and strange hallucinations, which may last for 30 minutes to 2 hours. When smoked, salvinorin A can produce a rapid and intense hallucinatory effect that of 10- to 15-minute duration.
Salvinorin A does not significantly increase heart rate or blood pressure. Typical recreational doses of salvinorin A increase plasma cortisol and prolactin. Loss of consciousness is common with very high doses, but no obvious harmful physical effects were observed in clinical studies with medium-range doses. Unpleasant aftereffects include tiredness, heaviness of head, dizziness, and “mental cloudiness” lasting for 24 hours or more after use. There are no reports of severe toxicity or deaths from overdose of salvinorin A. There is little evidence of S. divinorum causing psychiatric dysfunction beyond acute effects. There is no evidence of a withdrawal or addiction syndrome from salvinorin A, and an erratic and intermittent pattern of use is typical.
If taken orally, leafs or extracts containing salvinorin A have a mild effect, often compared to cannabis. There is a dissociative pattern of effects from higher doses, which appears suddenly within seconds and may last from 30 minutes to an hour or more, depending on dose. There is no significant euphoria, whereas dysphoria often occurs.
MDMA (“Ecstasy”)
MDMA (3,4-methylenedioxymethamphetamine) was first synthesized in Germany in 1912, and the American chemist Alexander Shulgin “rediscovered” MDMA in search for a psychotherapeutic in the late 1970s. MDMA was listed in 1986 as a schedule I drug in the United States and became a major drug of abuse, with a peak in the mid-1990s and a considerable mass of users to the present. Compared to the classical hallucinogen psilocybin, MDMA produces only minimal sensory effects (e.g., pseudohallucinations), but consistently increases feelings of elation. MDMA also has some amphetamine-like stimulant effects.
Maximum plasma levels after a typical oral dose of MDMA (1.6 mg/kg) are reached 1.5 to 2.5 hours after ingestion. Plasma levels decrease slowly over the following 10 hours. Excretion is >95% completed after 24 hours. A typical recreational dose (125 mg) has a half-life of approximately 8.5 hours. The major enzymes involved in the metabolism of MDMA are the liver cytochrome P-450 complex (CYP 450, CYP 2D6) and catechol-O-methyltransferase. Complex, nonlinear pharmacokinetics result from inhibition of CYP 2D6 and CYP 2D8 by MDMA and, in turn, results in much higher concentrations if users take consecutive doses. MDMA and its metabolites are excreted as conjugated glucuronides and sulfates through the kidneys, but >50% of MDMA is excreted unchanged in urine.
The first effects of MDMA are usually experienced within 30 minutes after an oral dose of 85 to 150 mg. The majority of individuals claim peak effects between one half to one hour after intake, with stronger effects in females. Somatic effects of MDMA include loss of appetite, diaphoresis, and bruxism. Dose-dependent increased blood pressure and heart rate also occurs, as well as increase in body temperature by 0.3°C to 0.4°C. MDMA has significant dose-dependent effects on the endocrine system, with increases in cortisol, prolactin, vasopressin, and growth hormone. MDMA acutely, but slightly, affects immunologic function. Additional side effects include nausea, jaw clenching, muscle tension, and blurred vision. A “hangover” for some hours or even 1 to 2 days can occur, with symptoms of insomnia, fatigue, sore muscles, headache, and decreased mood.
Intense pleasure and increased physical stamina are sought by dance party (“rave”) consumers of MDMA. Stimulant effects occur soon after ingestion, including increased energy and elevated mood. Side effects reported from such dance events are overexertion and elevated body temperature. In more extreme cases and/or environments, dehydration, hyperthermia, and tachycardia occur, and individuals may collapse from a potentially life-threatening hyperthermia (can lead to rhabdomyolysis and kidney failure), cardiac arrhythmia, and extreme exhaustion. Use of methamphetamine and cocaine in combination with MDMA increases the risk of serotonin syndrome. The lethal oral dose of MDMA in humans is calculated to be 1,875 mg.
Typical psychological reactions to MDMA in healthy, MDMA-naive adult research volunteers include improved disposition, increased physical well-being associated with vague symptoms of derealization and depersonalization, impaired thinking, and occasional feelings of anxiety with no or just slight increase in psychomotor drive. Subjects described a greater attention to feelings, a higher degree of openness, heightened empathy, and increased need for closeness with others. In controlled research settings, no health risks or significant complications have been reported.
Recreational use of MDMA may pose special risks. Increase of interpersonal openness and impulsivity may increase vulnerability to abuse. Especially more regular use of MDMA may induce prolonged anxiety and/or depression or in rare cases psychotic-like states, which may persist in some cases for days or weeks.
TOXICITY AND ADVERSE EFFECTS
Physical side effects of the clinically known indolealkylamines or phenylalkylamines are insignificant and do not lead to serious dysfunction of organ systems or brain damage. Their physiologic effects are usually very mild and limited to the acute phase of intoxication. Higher doses of pure smoked or injected DMT and some of the “newer” phenethylamines may be exceptions from this rule. Hallucinogens induce no lasting damage or neurophysiologic alterations but can cause seizure and accidents from incoordination.
Adverse effects with the classical hallucinogens are not very frequent and result mainly from “bad trips,” that is, severe anxiety or paranoid reactions, or perceptual distortions, delusions, and hallucinatory effects. Accidents may happen because of distorted reality, especially with higher doses and potent substances like salvinorin A.
A clinically significant long-term aftereffect, occurring in a minority of users (estimated 1% to 10%), is so-called flashbacks, that is, the reexperiencing of some fragments of the original hallucinogen experience. This may happen when a traumatic experience with a hallucinogen occurred previously. There is no evidence of lasting effects on neurocognitive functioning or teratogenic effects of hallucinogens in humans. Mutagenic effects of LSD were suggested by some early in vitro experiments but have been disproven by later studies.
The situation is different with entactogens such as MDMA. High-dose regimens in animals suggested neurotoxicity, although the data are inconsistent, especially in humans. Destructive effects of entactogens on the serotonergic system have been shown in animal studies, usually with very high doses. Chronic users of MDMA, who do so in combination with other psychoactive substances, show decreased serotonin transporter density in the brain. Other indications of serotonergic neuron impairment depend on the cumulative doses. People with lifetime use of 50 to 100 doses of MDMA and heavier users, who did not combine ingestion with other substances, exhibit no alteration in diverse neurometabolic and neuropsychological measures. More evidence for memory impairment and serotonergic alterations has been reported in MDMA polydrug users.
DRUG–DRUG INTERACTIONS
Most prescribed medications do not significantly interact with the classical hallucinogens. Psychopharmacologic agents like tricyclic antidepressants and lithium may increase responses to LSD, while selective serotonin reuptake inhibitors (SSRIs) and MAO inhibitors decrease the subjective LSD response. Chronic tricyclic antidepressant administration was associated with increases in physical and psychological responses to LSD. Effects of MDMA are attenuated by SSRIs and serotonin–norepinephrine reuptake inhibitors. Serious complications from combinations of MDMA with antiretroviral agents were reported. Coingestion of other stimulants may worsen side effects of MDMA and classical hallucinogens. LSD slightly potentiates the effects of MDMA. Alcohol can attenuate but also prolong euphoric effects of MDMA, decreases MDMA-induced hyperthermia, but does not alter its cardiovascular effects. Regular use of MDMA and methamphetamine reduces striatal DA transporters more than MDMA alone.
NEUROBIOLOGY
Hallucinogens exert an activating effect on parts of the CNS due to their agonist properties at serotonergic, adrenergic, and dopaminergic neurotransmitter-modulated brain systems. The 5-HT2A receptor appears to be the primary site of action for the indolealkylamine and phenylalkylamine hallucinogens, with significant modulation by other serotonergic sites including 5-HT2C and 5-HT1A receptors. Hallucinogens enhance glutamatergic transmission in the cortex. Activation of 5-HT2A leads to increased cortical glutamate levels, probably mediated by thalamic afferents, which may alter corticocortical and corticosubcortical transmissions. Glutamate release triggered by 5-HT2A receptor activation may represent a major final common pathway for the actions both of serotonergic and glutamatergic hallucinogens.
Amphetamines (including some with entactogenic effects) are potent DA-releasing agents. However, the psychoactive effects of entactogens are at most only minimally mediated via the dopaminergic system. The prevailing theory is that the psychoactive effects of entactogens are mediated by potent synaptic release as well as reuptake blockade of the neurotransmitter serotonin that, in turn, results in increased intrasynaptic serotonin.
RELATIVE ADDICTION LIABILITY
Use of hallucinogens very rarely meets the ICD-10 or DSM-V criteria for a substance use disorder. Community-based epidemiologic studies in the United States suggest that <3% of past-year hallucinogen users develop dependence, with another fifth developing abuse. Virtually, all of the hallucinogenic drugs lack affinity either for DA receptors or for the DA uptake transporter and therefore do not directly affect DA neurotransmission. The classical hallucinogens, as well as salvinorin A, have negative reinforcing properties in animal studies. Additionally, all classical hallucinogens induce tolerance relatively immediately. Therefore, more frequent use will lead to little or no acute intoxication after a very short period of use, possibly discouraging extended periods of frequent use. The entactogens, like MDMA, lead to a massive depletion of intracellular serotonin. Therefore, the serotonin storage is emptied and no entactogenic effects will occur after a very few daily ingestions. Meanwhile, the more amphetamine-like effects from entactogens (which are not dependent on serotonin, but rather on norepinephrine and DA) still occur: psychophysical excitation, anorexia, overarousal, restlessness, and sleeplessness. MDMA therefore has some reinforcing effects but significantly less than methamphetamine and cocaine.
KEY POINTS
1. Hallucinogenic substances influence information flow throughout the brain, thereby inducing an altered state of mind that affects conceptual cognition, affectivity, and sensory processing.
2. Classical hallucinogens (e.g., LSD, psilocybin, DMT) do not induce physical dependence or a withdrawal syndrome and therefore users very rarely will meet most of the ICD-10 or DSM-V criteria for a substance use disorder.
3. Main complications result from unsupervised use of hallucinogens and may lead to serious problems. The only clinically significant long-term aftereffects, occurring in a minority of users (estimated 1% to 10%), are so-called flashbacks, that is, the reexperiencing of some fragments of the original hallucinogen experience.
4. The 5-HT2A receptor appears to be the primary site of action.
REVIEW QUESTIONS
1. What is the preferred medication within the ED for a “bad trip”?
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