Background
Hallucinogens are a diverse group of drugs that cause an alteration in perception, thought, or mood. A rather heterogeneous group, these compounds have different chemical structures, different mechanisms of action, and different adverse effects. Despite their name, most hallucinogens do not consistently cause hallucinations, which are defined as false sensations that have no basis in reality. Often, they are more likely to cause changes in mood or in thought than actual hallucinations.
Hallucinogens share a rich history. Many cultures have used hallucinogens for religious or mystical experiences. The Hindu holy book, Rig Veda, mentions soma, a sacred substance used to induce higher levels of consciousness. Soma is thought to have been derived from the juice of the hallucinogenic mushroom Amanita muscaria as depicted in the image below. The Aztecs in pre-Columbian Mexico described the ceremonial use of teotlaqualli, a paste made from the hallucinogenic flower, ololiuqui. Rubbed on the skin of Aztec priests and soldiers, it was thought to eliminate fear and place the user in a proper mental state to serve the Aztec gods. The Mexican Indians have a long history of using peyote, a mescaline-containing hallucinogen, in religious ceremonies. Hallucinogens have also been proposed as a cause of the "immoral and illicit" behavior of alleged witches in the Salem, Massachusetts witch trials.
View Image | Hallucinogens. Amanita muscaria. |
The first synthetic hallucinogen, lysergic acid diethylamide (LSD) 25, was serendipitously discovered in 1938 by Sandoz laboratories while searching for a new ergot-derived analeptic agent. Its discoverer, a Swiss chemist named Albert Hoffman, began to experience hallucinations after an inadvertent percutaneous exposure to the drug. Sandoz began marketing the new drug in 1947. Delysid, as the drug was called, was used by psychiatrists who believed its use in psychotherapy could help the patient access repressed emotions. The US Central Intelligence Agency also conducted human experiments with LSD, testing its use as an interrogation tool and as a mind-control agent. Unfortunately, many of these studies were conducted without the consent or knowledge of the participant.
LSD use increased in the late 1950s and early 1960s. Popularized by the media and by people such as Timothy Leary, experimentation with psychedelics reached a peak in the mid 1960s. As use increased, adverse reactions began to be reported. In 1966, because of mounting public health concerns, the federal government banned LSD. Illicit manufacture and use of hallucinogens, of course, has continued.
Hallucinogen use declined in the 1970s and early 1980s. Recent studies show an increase in use during the 1990s, particularly in the high school and college-age population. LSD is presently classified as a schedule I drug, ie, an agent with high abuse potential and no documented medical indication.
Pathophysiology
Hallucinogens may be grouped by structural criteria. The main groups include lysergamides, phenylethylamines, piperidines, indolealkylamines, and cannabinols.
Drugs classified as hallucinogens (abbreviated)
See the list below:
Lysergamides
Lysergic acid diethylamide
Lysergic acid hydroxyethylamide (in morning glory seeds and Hawaiian baby woodrose)
Indolealkylamines
Psilocybin
Psilocin
Bufotenin
Dimethyltryptamine (DMT)
Alpha-methyltryptamine (AMT)
5-methoxy,-N,N-dimethyltryptamine (5-MeO-DMT)
5-methoxy,-N,N-diisopropyl-tryptamine (5-MeO-DIPT)
Phenylethylamines
Mescaline
Methamphetamines
3,4-methylenedioxymethamphetamine (MDMA)
3,4-methylenedioxyethamphetamine (MDEA)
3-methoxy-4,5-methylenedioxyamphetamine (MMDA)
4-methyl-2,5-dimethoxymethamphetamine (DOM)
Piperidines
Ketamine
Phencyclidine (PCP)
Cannabinols - Tetrahydrocannabinol (marijuana, hashish)
Others - Anticholinergics (including atropine and scopolamine), GABA receptor agonists, ibotenic acids, and muscimol from the mushrooms Amanita muscaria and Amanita panthenia
Lysergamides
The lysergamides include LSD and lysergic acid hydroxyethylamide, which is a naturally occurring psychedelic found in morning glory seeds. LSD was initially derived from the ergot alkaloids produced by the fungus Claviceps purpurea as shown below , a contaminant of wheat and rye flour. LSD is the most potent psychoactive drug, with doses as low as 1-1.5 mcg/kg capable of producing psychedelic effects. Despite its potency, LSD has a very large safety margin; no deaths associated with isolated LSD ingestion have been reported, despite ingestions of several thousand mcg.
View Image | Hallucinogens. Claviceps purpurea. |
A tasteless, colorless, odorless liquid, LSD is usually sold as liquid-impregnated blotter paper, gelatin squares (window panes), or tiny tablets (microdots). Although usually ingested in blotter form, LSD can also be taken via intranasal, sublingual, parenteral, inhalational, or even conjunctival (ie, eyedrops) routes. LSD has dozens of street names, many referring to the pattern printed on the blotter paper, including acid, 'cid, sorcerer's apprentice, paper acid, Lucy in the Sky with Diamonds, Beavis and Buttheads, Bart Simpsons, and Sandoz. Typical street doses are 20-80 mcg of LSD per dose. This is much less than the levels reported during the 1960s and early 1970s, when the doses ranged from 100-200 mcg or higher, per unit.
LSD acts on serotonin and dopamine receptors in the brain. The neurotransmitter serotonin modulates mood, pain, perception, personality, sexual activity, and other functions. The hallucinogenic activity of LSD is thought to be mediated by LSD's effect on serotonin-2 receptors. LSD acts postsynaptically to inhibit serotonin release and increase retention of serotonin at serotonin-2 receptors. Its net effect is that of a serotonin agonist.
The onset of psychological effects occurs approximately 30-60 minutes after ingestion of LSD, and they last for approximately 12 hours. Effect peaks at approximately 5 hours. The psychological effects vary both with the individual taking the drug and the physical environment surrounding the user.
Several common elements of the "trip" are recognized. Changes in mood and perception are uniform. Boundaries between users and their environment are blurred, time becomes distorted, stationary objects may seem to flow or pulsate, and color perception is heightened. Synesthesias, such as hearing color or seeing sounds, are commonly reported. A feeling of clarity of consciousness may be reported by the user, during which the importance of reality is diminished. Hallucinations may occur, although users are usually aware that they are hallucinating. Occasionally, a threatening or stressful environment may provoke feelings of severe anxiety and paranoia. This acute panic reaction is often referred to as a "bad trip" and is the most common reason for users to seek medical attention.
A transient depression may occur after LSD use. Acute psychosis after LSD use has been reported, and an underlying or undiagnosed schizophrenia may worsen. An unusual aspect of LSD use is the occurrence of "flashbacks," or hallucinogen persisting perception disorder (HPPD), months to years after LSD use.[1] These are observed most commonly in persons who have used LSD more than 10 times. During a psychotic episode, danger of suicide and homicide exists.
In addition to the psychological effects, LSD also produces sympathomimetic effects. Increases in heart rate, blood pressure, and, occasionally, temperature may occur. Mydriasis usually occurs and appears to parallel the intensity of the trip, with pupils returning to normal when the patient returns to a non–drug-induced mental state. Rarely, LSD can produce life-threatening symptoms. Hyperthermia (particularly with monoamine oxidase [MAO] use), hypertension, coma, respiratory arrest, and bleeding have been reported. However, users remain more at risk from behavior-related trauma than they do from the toxic effects of the LSD.
Lysergamides are also found naturally in several species of morning glory (Rivea corymbosa, ololiuqui) and Hawaiian woodrose (Ipomoea violacea) as depicted in the image below. The seeds of these plants contain lysergic acid hydroxyethylamide, which has approximately one tenth the potency of LSD.
View Image | Hallucinogens. Morning glory (Ipomoea violacea). |
Phenylethylamines
Phenylethylamine derivatives include mescaline and several hallucinogenic amphetamines. Mescaline is the psychogenic amphetamine found in the peyote cactus, Lophophora williamsii. Native Americans have used peyote for more than 8000 years. Use continues today; members of the Native American Church are still permitted to use the drug in religious ceremonies. Mescaline is thought to induce hallucinations by an amphetaminelike action, although the precise mechanism is unknown. After ingestion of 6-12 peyote buttons (the dried bitter fleshy tops of the cactus), the user first begins to feel effects in 30 minutes to 2 hours. Nausea, vomiting, diaphoresis, and ataxia precede the hallucinogenic effects, which may last 8-12 hours. Mescaline also may be sold as pills containing ground peyote or a synthetic congener, but the prohibitively high cost of the raw materials often leads many dealers to simply substitute PCP.
The hallucinogenic amphetamines, also known as enactogens (ie, enabling the user to "touch within"), are structural analogs of mescaline and amphetamine. Most were derived from their parent compounds in an effort to avoid US Drug Enforcement Agency prosecution (so-called designer drugs). They all have similar psychogenic effects and toxicity. They include MDMA, MDA, MDEA, and MMDA.
MDMA, also known as ecstasy, is perhaps the most well known of these compounds. First synthesized in 1914, MDMA is presently the drug of choice at "raves," ie, all-night dance parties popular in the United States and the United Kingdom. MDMA appears to affect serotonin neurotransmission at presynaptic and postsynaptic sites.
A study by Erritzoe et al suggests MDMA use is associated with changes in the cerebral presynaptic serotonergic transmitter system and that subcortical, but not cortical, recovery of serotonin transporter (SERT) binding might take place after several months of MDMA abstinence.[2]
Although it usually does not cause hallucinations, it causes changes in mood and the perception of music, reputedly increases interpersonal communication, and fosters feelings of intimacy and empathy. Despite these positive-sounding attributes, concern is growing that ecstasy use may cause permanent neural damage to its users.
Animal and primate studies show significant degradation of serotonergic neurons following MDMA use.[3] This degradation is cumulative and dose-related. This has led some experts to warn of the possibility of permanent mood disorders in individuals who use the drug regularly. Wilcox et al studied 2 young men who chronically abused MDMA and later developed movement disorders typical of Parkinson disease.[4]
In terms of complications and overdoses, the hallucinogenic amphetamines do not seem as benign as other psychedelic drugs. Many of their toxicities are identical to those of amphetamines. Sympathomimetic effects predominate, with hypertension and tachycardia being quite common. Hyperthermia is a common and occasionally serious complication. The combination of sympathomimetic effect, strenuous physical activity, dehydration, and high ambient temperatures found at raves all contribute to severe hyperthermia. This also may be accompanied by rhabdomyolysis, myoglobinuric renal failure, and disseminated intravascular coagulation (DIC).
Several deaths have been reported with MDMA use. Media coverage of these deaths has resulted in the belief that water is the antidote to MDMA. Unfortunately, the consumption of large amounts of water, combined with an intrinsic SIADH-like (syndrome of inappropriate secretion of antidiuretic hormone) effect of the drug itself, often leads to hyponatremia and, occasionally, seizures. Other reported complications of MDMA use are MAOI–induced hypertensive crisis, serotonin syndrome, seizures, hepatotoxicity, and tachydysrhythmias. Frequent users rapidly develop tolerance to the drug, requiring higher doses for the same effect.
Piperidines
Piperidine derivatives include PCP and ketamine. PCP was developed in the late 1950s as a dissociative anesthetic/analgesic agent initially marketed under the brand name Sernylan. It was soon withdrawn from use because of severe adverse psychological reactions following its use; severe dysphoria, agitation, and psychotic behavior were all noted routinely. It was used in veterinary medicine in the 1960s and soon became a popular drug of abuse, first observed in San Francisco. During a psychotic episode, danger of suicide and homicide exists.
Dubbed the PeaCe Pill, or PCP for short (also known as angel dust), its dysphoric effects and erratic absorption initially limited its appeal. However, its popularity eventually increased as dealers misrepresented the cheap and easy-to-synthesize drug as delta-9-tetrahydrocannabinol (THC), mescaline, LSD, or amphetamines. PCP continues to be marketed in place of other harder-to-obtain drugs. Use peaked in the late 1970s, declined in the 1980s, but seems to have made a resurgence in the 1990s. PCP goes by several street names, including angel dust, killer weed, elephant tranquilizer, rocket fuel, and hog.
The onset of effects occurs in 2-5 minutes after ingestion or smoking of PCP (often it is sprinkled on marijuana cigarettes). Peak effect occurs by 15 minutes. The duration of action is as long as 16 hours (some users report effects persisting as long as 24-48 h). PCP antagonizes the action of glutamate at the N-methyl-D-aspartate receptor, blocking the influx of calcium and inhibiting neurotransmitter release. Depending on the dose, PCP may cause either CNS excitation or depression. Sympathomimetic effects are prominent.
The clinical manifestations of PCP use are extremely variable and unpredictable. The patient may appear calm or wild, disoriented, violent, stuporous, or comatose, depending on the ingested dose. Patients often have a blank stare. Ataxia, grimacing, bruxism, muscle rigidity, and myoclonus are common. Temperature, heart rate, and blood pressure are elevated. Bizarre and psychotic behaviors are often noted. PCP is associated with a much higher morbidity and mortality than other classes of hallucinogens. The combination of sympathetic effects, severe agitation, and muscle rigidity place these patients at high risk for the complications of severe hyperthermia, rhabdomyolysis, and subsequent myoglobinuric renal failure. Their violent and bizarre behavior places them at high risk for trauma. The dissociative nature of PCP allows users to do tremendous harm to their bodies with little or no perceived pain.
Ketamine, structurally similar to PCP, is currently a widely used dissociative anesthetic. Abused since the 1970s, ketamine is currently undergoing a resurgence in popularity. Called "Special K," it is a popular drug at raves.
Indolealkylamines
The indolealkylamine group includes the 2 mushroom-derived hallucinogens (ie, psilocybin, psilocin), DMT, and bufotenine. They all appear to cause their psychogenic effects through activity at the serotonin receptor. Psilocybin is found in the following 3 major genera of mushrooms: Psilocybin, Conocybe, and Panaeolus. Often growing on cow dung, they are found in most areas of the United States, with the exception of arid regions. Several drug-oriented magazines advertise home cultivation kits that include live mycelia. The effects of psilocybin last approximately 4-6 hours. Hallucinations are common. The mushrooms cause fewer adverse reactions than LSD, although cases of hyperthermia, seizures, and coma have been reported. Misidentification of the mushrooms in the wild and on the street is common; only one third of "magic mushrooms" bought on the street contain psilocybin. Many are simply store-bought mushrooms laced with PCP.
DMT is a potent psychedelic with a brief duration of action (15-60 min). This has earned it the nickname "businessman's trip." It is found naturally in the bark of trees of the genus Virola, which grows in the Amazon basin. DMT is only active when smoked or snorted. It causes more visual hallucinations and more sympathetic effects than LSD.
Several species of toads produce venom that has psychoactive properties. Members of the genus Bufo, particularly Bufo marinus (see the image below) and Bufo alvarius, contain bufotenine and 5-MeO-DMT. The compound 5-MeO-DMT is firmly established as a hallucinogen, whereas the role of bufotenine has not yet been established. The toads are either licked or milked for their venom, which may then be ingested or smoked. Their dried skin also may be smoked.
View Image | Hallucinogens. Bufo marinus. |
Synthetic 5-MeO-DIPT, (Foxy, Foxy Methoxy, or fake ecstasy) has experienced a recent surge in popularity and is frequently publicized as an erotic enhancer. It has hallucinogenic properties that are similar to other tryptamine compounds and is known to be mildly euphoric.
AMT has also been emerging in the club and rave scenes and is often sold in conjunction with 5-MeO-DIPT.
Cannabinols
Marijuana is the leaf or flower of the plant Cannabis sativa and is commonly known as pot, grass, or weed. It contains the psychoactive substance THC. Although usually grouped with other hallucinogens, marijuana rarely causes hallucinations. Acute effects from smoking marijuana include an alteration in perception or mood, laughing, increased appetite, conjunctival injection, tachycardia, and mild CNS depression. See Medscape Reference article Cannabis Compound Abuse.
Other hallucinogens
Several mushrooms of the genus Amanita possess hallucinogenic effects. These include Amanita muscaria, Amanita pantherina, and Amanita cothurnata. These are not to be confused with the deadly Amanita phalloides group. A muscaria (see the image shown below) , or fly agaric, has been used as a psychotropic by Siberians for centuries. The active substances in the mushroom, muscimol and ibotenic acid, are thought to act on GABA receptor sites. The drug is excreted unchanged in the urine, leading to the Siberian practice of drinking the urine of persons or reindeer that have eaten the mushroom. Effects begin approximately 20 minutes after ingestion and last for 6-12 hours. Visual hallucinations and mania alternate with periods of deep sleep.
View Image | Hallucinogens. Amanita muscaria. |
Despite its name, A muscaria contains only a small amount of muscarine and does not cause cholinergic toxicity.[5]
Treatment with atropine is contraindicated, especially given that anticholinergic substances can also be hallucinogens. In particular, the plant family S olanaceae (nightshade) contains atropine and scopolamine which cause hallucinations, which are often unpleasant and dissociative in nature.
Physical
A complete set of vital signs should be obtained. Hallucinogen use may manifest with tachycardia, hypertension, and hyperthermia. Hypotension, hypoxia, and marked tachycardia or bradycardia are strong clues that imply serious disease.
Sympathomimetic effects are common and often precede the hallucinogenic effects. Findings may include mydriasis, tachycardia, sweating, hyperthermia, ataxia, and vomiting. Note pupil responses where appropriate.
Perform a complete mental status examination on all patients.[9] Affect, speech, appearance, presence of auditory/visual hallucinations, delusional thinking, and suicidal/homicidal ideation should be carefully assessed.
Most persons experiencing the effects of a hallucinogen are awake, alert, and oriented. Obtunded patients or those with a focal neurologic examination should prompt an aggressive search for an organic etiology.
Although nystagmus in any direction can occur with PCP use, rotatory nystagmus is a classic sign.
Trauma resulting from drug-induced behavior is common.
Conjunctival injection is commonly observed with marijuana use.
Toad licking may cause profound drooling, seizures, and cyanosis.
Severe hyperthermia may be observed with PCP or MDMA use.
The subjective experience of using a hallucination can vary tremendously, not only person to person, but also between ingestions. This makes violence potential difficult to predict. Nevertheless, PCP is generally considered to have the most potential for violence and suicidal or homicidal behavior.[10]
Medical Care
As with any toxic ingestion, proper attention first should be directed to the assessment and stabilization of the patient's airway, breathing, and circulation.
For any person presenting with hallucinations or psychosis, even if a hallucinogen is strongly suggested as the inciting agent, the basic approach to a patient with altered mental status should be followed. This includes administration of dextrose (or demonstration of a normal blood glucose level), thiamine, and naloxone. Other etiologies for the patient's symptoms should not be discounted.
Prehospital care providers should attempt to ascertain the type and amount of hallucinogen ingested and the presence of any other co-ingested drugs or psychoactive substances.
A basic principle in the care of persons who have ingested hallucinogens is calm reassurance. Patients presenting with an acute panic reaction should be placed in a quiet nonthreatening environment with minimal stimuli. Reassure patients that their anxiety is caused by the drug and that the effect will wear off in several hours. However, patients that are medically stable but 1) remain anxious or agitated, 2) have continued hallucinations 3) remain a danger to themselves or others, or 4) would not be able to care for themselves after several hours of observation, should be admitted to a psychiatric hospital.
Patients should be physically or chemically restrained if they are a danger to themselves or others. However, avoid prolonged or excessive physical restraint because this can contribute to hyperthermia, rhabdomyolysis, and acidosis, and it can exacerbate the patient's paranoia. Aggressive cooling measures (fans and mist) should be undertaken if significant hyperthermia is noted. In severe cases, paralyzation and endotracheal intubation should be undertaken. Rhabdomyolysis, if diagnosed, should be treated with fluid repletion and alkalinization of the urine.
Benzodiazepines are the cornerstone of treatment for anxious or agitated patients. They reduce anxiety and the sympathomimetic effects of hallucinogens.
Phenothiazines should be avoided. They may reduce the seizure threshold, and their anticholinergic effects only serve to worsen the patient's hyperthermia and tachycardia.
The role of butyrophenones, particularly droperidol and haloperidol, is less clear. Condemned by some as epileptogenic, they remain in wide use to chemically restrain violent and psychotic patients.
The hypertension and tachycardia associated with hallucinogens rarely require any treatment beyond a benzodiazepine. In the rare case of severe hypertension or tachycardia, treatment with nifedipine or nitroprusside may be indicated. Avoid beta-blockers because many of these drugs have both alpha- and beta-adrenergic effects. Isolated beta-blockade leads to unopposed alpha-adrenergic activity, worsening the hypertension and increasing mortality.
Author
Brooke S Parish, MD, Associate Professor, Department of Psychiatry, University of New Mexico School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Michael E Richards, MD, MPA, Associate Professor and Chair, Department of Emergency Medicine, University of New Mexico School of Medicine
Disclosure: Nothing to disclose.
Scott Cameron, MD, Consulting Staff, Department of Emergency Medicine, Regions Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Eduardo Dunayevich, MD, Executive Director, Clinical Development, Amgen
Disclosure: Received salary from Amgen for employment; Received stock from Amgen for employment.
Acknowledgements
Ronald C Albucher, MD Chief Medical Officer, Westside Community Services; Consulting Staff, California Pacific Medical Center
Ronald C Albucher, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: Nothing to disclose.
){kind=link}
){kind=link}
){kind=link}
){kind=link}