Serotonergic Hallucinogens


This chapter focuses on hallucinogens with psychoactive properties mediated through the serotonin system. Although commonly referred to as “hallucinogens,” a lexigraphic disclaimer is warranted, as the experience elicited by these drugs commonly centers on distortion of perception, not true hallucinations. The most apt term is probably “psychedelic” from the Greek psukhē , meaning “mind” and dēloun, meaning “reveal” or “make visible.” Although the enlightenment sought by recreational users may be an artifact of the psychoactive experience, researchers study these compounds hoping to gain insight into how the brain produces the mind. Nonetheless, in conforming to common usage, in this chapter these drugs will be referred to as hallucinogens.


Perceptions provide reassurance into our existence and the existence of the world around us. Thus it is not surprising that compounds capable of producing altered states of perception are regarded with mystical fascination and trepidation. The ritualistic consumption of plants, many of which derive their psychoactive properties through the serotonin system, has been an important part of religious and social ceremonies throughout human history.

Conceivably the oldest known ritualistic use of hallucinogens was in the Indus Valley during the second millennium BCE. A group of people known as Aryans worshiped a deity they named “Soma,” which recent evidence suggests is the mushroom Amanita muscaria or Fly agaric. These served as an inspiration to several later cultural sources: Aldous Huxley refers to soma as the “ideal pleasure drug” in his novel Brave New World, and the red and white spotted mushroom that is A. muscaria incidentally bears resemblance to the mushroom featured in the Mario Brothers video game worshipped by many adolescents in the second millennium CE.

Spiritual use of hallucinogens has been a part of various cultures throughout the world. In the 14th century CE, Aztecs and other Indians of Central America ingested psilocybin-containing mushrooms to bestow powers of clairvoyance during religious ceremonies. Contemporary South American and Caribbean peoples snorted a narcotic powder (Cohoba), which, reminiscent of modern club drugs, was used to promote friendliness during convulsive dance ceremonies. In Western cultures, hallucinogens may underlie mythos of witchcraft and sorcery. In his book Hallucinogens and Shamanism , Michael Harner relates the symbol of a witch riding on a broomstick to the practice of medieval women achieving magical powers by anointing their mucous membranes with hallucinogenic substances. Linnda Caporael hypothesized that that the affliction of the girls sparking the Salem witch trials resulted from ergot (the natural substance from which lysergic acid diethylamine [LSD] is derived) poisoning caused by ingestion of rye grains contaminated with the fungus Claviceps purpurea . More recently, a study conducted by Griffiths et al. found that when administered under supportive conditions psilocybin occasioned experiences similar to spontaneously occurring mystical experiences.

The modern synthetic drug era began in the late 1960s with the legendary synthesis of LSD by the Swiss chemist, Albert Hoffman. While working at Sandoz Laboratories, Hoffman synthesized LSD as part of an effort to develop ergot derivatives capable of reducing postpartum bleeding. Not useful in this regard, the compound was shelved. Five years later, according to psychedelic lore, Hoffman was haunted by a “peculiar presentment” and repeated its synthesis. After accidentally absorbing a small amount he experienced its psychoactive effects while bicycling home. Psychedelic enthusiasts refer to this fateful day, April 16, 1943, as “Bicycle Day.”

In the 1960s and 1970s, Timothy Leary brought LSD and other psychedelics to the forefront of pop culture. His introduction of psychedelic drugs to academic and therapeutic settings led to the research responsible for most of what is currently known about these drugs. However, his temerarious promotion of these drugs for individual enlightenment and the ensuing underground abuse precipitated strict government regulation, which for several decades halted substantial scientific research. In the 1980s, attention to hallucinogen use reemerged with the trend of all night dance parties known to as raves. These large gatherings featured electronic dance music and laser light shows. Attendees often used psychedelic drugs (most commonly 3,4-methylenedioxymethamphetamine—also known as MDMA or Ecstasy) to promote sociality and heighten the sensory stimuli of the music and lights. Despite the emergence of new hallucinogens, the use of LSD and the traditional psychedelics continued throughout recent decades.

Today, restrictions on research have loosened and there is a gradual increase in obtaining approval and carrying out research on psychedelic drugs. In recent years, emerging evidence is accumulating, indicating that serotonergic hallucinogens may be useful in a variety of clinical situations, such as treating cluster headaches, anxiety associated with life-threatening diseases, and substance use disorders. Alongside the increased prevalence of hallucinogen use for individual enlightenment and therapeutic potential, concerns regarding potential adverse effects of these drugs increased as well. These include both physiological effects, which in some cases led to severe adverse effects (e.g., cases of seizures, cardiac arrhythmia, and death following ibogaine use ), as well as psychiatric adverse effects (e.g., include anxiety, flashbacks, psychosis following LSD use ). Accordingly, the use of hallucinogens for personal and spiritual growth was gradually met with concerns surrounding abuse of these substances, and particular concerns regarding their potential adverse effects.


Hallucinogen use has declined since the 1970s, with the annual prevalence remaining below 10%. The types of hallucinogens used have also changed. LSD, which was the most widely used hallucinogen, has been surpassed by newer synthetic club drugs. In 2014, the Substance Abuse and Mental Health Services Administration (SAMHSA) reported findings from the National Survey on Drug Use and Health (NSDUH), indicating that use of hallucinogens has remained relatively steady since 2002. In 2014, 1.2 million people in the United States (0.4% of the population) reported using hallucinogens in the past month (use was higher among males compared to females: 748,000 vs. 426,000). In the same year, there were 936,000 people 12 years of age or older in the United States who had used hallucinogens for the first time within the past 12 months. According to the same report, the most common hallucinogen used was MDMA, with 609,000 people 12 years or older reporting use in the past month.


Serotonergic hallucinogens can be divided by chemical structure ( Fig. 31.1 ). Indolealkylamines, which have more than one carbon ring and are structurally similar to serotonin, include LSD, ibogaine, psilocin, psilocybin, and N,N -dimethyltryptamine. The phenethylamines, that have only one carbon ring, more closely resemble amphetamine and the catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine). This class comprises mescaline, MDMA, 3,4-methylenedioxyamphetamine, and dimethoxymethylamphetamine. The psychopharmacology of all of the serotonergic hallucinogens (except for MDMA) is similar.

Fig. 31.1

Chemical structures of indolealkylamine and phenethylamine hallucinogens.

To avoid redundancy, this chapter begins with a general discussion of mechanism of action and then concentrates on representative indolealkylamines (LSD, psilocybin, and ibogaine) and phenethylamines (mescaline and MDMA), with LSD serving as a prototype for comparison.

Mechanism of Action

After nearly a half a century of research, it is currently understood that the psychoactive effects of both indolealkylamine and phenethylamine hallucinogens are mediated primarily through agonist activity at the 2A subtype of serotonergic receptors (as serotonin is also known as “5-hydroxytryptamine” [5HT], these are known as 5HT2A receptors). The structural resemblance of indolealkylamines to the serotonin neurotransmitter led researchers to suspect that their psychoactive effects were serotonergically mediated. Furthermore, the reported similarity of psychic experiences elicited by the phenethylamines and the indolealkylamines, as well as cross-tolerance between the two classes, suggest a shared mechanism of action, although distinct effects via distinct psychodynamic activity are yet to be understood.

Serotonin Receptor

The monoamine family of neurotransmitters comprises serotonin, epinephrine, norepinephrine, and dopamine. The serotonin receptor system is particularly complicated, with 14 distinct receptors belonging to 7 families (5HT1R–5HT7R) having been discovered so far. The system is made more complex by posttranslational receptor modifications, multiple G proteins, phenotypic switching, and crosstalk within and probably between receptor families. All but one of the serotonin receptors are coupled to G proteins. The 5HT2A and 5HT2C receptors are similar and often referred to as the 5HT2A/2C receptor. There is a paucity of ligands with selectivity between these two subtypes, making it difficult to rule out an ancillary role of 5HT2C receptors in the psychoactive effects of hallucinogens.

Indolealkylamine Hallucinogens

Lysergic Acid Diethylamide (LSD)

Street Information

Today, the majority of LSD is synthetic. However, it can be derived from two naturally occurring substances; the embryo of morning glory seeds ( Rivea corymbosa ) and C. purpurea (the parasitic fungus mentioned in the preceding text). Sunlight and chlorine—even at tap water concentrations—will inactivate LSD but it can be stored as a solid salt or dissolved in pure water as long as it is kept at low temperatures and protected from light and air. Synthetic LSD is crystalline. It is crushed into a white odorless, tasteless powder that is dissolved and administered orally, sublingually, intramuscularly, or intravenously. Sublingual mediums include postage stamps, chewing gum, or sugar cubes often decorated with symbols ( Fig. 31.2 ).

Fig. 31.2

Photograph of lysergic acid diethylamide (LSD) blotter sheet.

From the US Drug Enforcement Administration website.

Street names for LSD, as for all of the serotonergic hallucinogens, are creative and include, but are not limited to, “acid,” “blotter,” “dots,” and “Lucy.” LSD is extremely potent and can even be absorbed subcutaneously. Doses of 20–30μg produce psychoactive effects in humans, and Hoffman estimated it to be 5000 to 10,000 times more potent than mescaline. Although there is no standard dose for lysergic acid, the range of doses taken for recreational purposes is generally between 50 and 400 μg, considerably lower than in the 1970s. LSD is easily produced in great quantity. For example, 25 kg of ergotamine tartrate (a substrate for LSD) yields 5 kg of LSD or 100 million doses.

Physiological and Psychological Effects

LSD is hepatically metabolized and has no active metabolites. Maximal concentrations are reached between 0.5 and 4 hours after administration. Concentrations then decrease following first-order kinetics with a half-life of about 3.5 hours and slower elimination thereafter with a terminal half-life of close to 9 hours. In a clinical study administering 200 μg to human subjects, 1% of the orally administered LSD was eliminated in urine as LSD, and 13% was eliminated as 2-oxo-3-hydroxy-LSD within 24 hours. No sex differences were observed in the pharmacokinetic profiles of LSD. The acute subjective and sympathomimetic responses to LSD lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. Users of LSD typically experience autonomic symptoms within several minutes and psychoactive effects approximately 10 minutes later. The autonomic symptoms are mainly sympathomimetic, that is, elevated blood pressure and pulse, diaphoresis, piloerection, nausea, uterine contractions, hyperreflexia, and tremor. Anisocoria (unequal pupils) and hippus (rhythmically dilating pupils) are not uncommon.

Lysergic acid has several effects on psychological experience, including heightened mood, increased optimism, and trait-openness. Additional reports of spiritual experiences and altered consciousness are common. Recent neuroimaging studies show increased global connectivity in high-level association cortices and the thalamus under the drug. The increase in global connectivity observed under LSD correlated with subjective reports of “ego dissolution.”

Not only does mood become amplified under the influence of LSD, but it can shift rapidly, and some users have reported experiencing multiple moods simultaneously. In addition, an increase in scores of psychotic-like symptoms are observed. Sensory perceptions become enhanced and distorted. Typical descriptions include vivid colorful geometric shapes, trails of actual objects, and seeing body parts separate from themselves. Dramatic complex disturbances may occur such as animation of inanimate objects or Satan’s face appearing on someone’s body. Auditory distortions are less common. At higher doses, synesthesia may occur (perceiving a sensation in different modality such as hearing colors). Distortions in the sense of time include time halting, stretching, repeating, and ceasing to exist.

When the overall experience is perceived as enlightening or emotionally stimulating, it is referred to as a “good trip.” Other times the experience might be nightmarish, with fears of insanity or losing control. Such negative experiences are referred to “bad trips.” While it has long been suggested that “set” (the individual’s mindset) and “setting” (the physical and social environment) substantially affect psychedelic experience, it is unclear precisely what role they play in the cause of good trips versus bad trips. The clear association between the nature of a trip under the influence of LSD and subsequent experiences (good or bad) following ingestion is also unknown.

Hallucinogen Use Disorder

Tolerance to the psychological effects of LSD, but not the physiological effects, develops quickly. In contrast to highly addictive drugs such as cocaine and heroin, with LSD there does not appear to be a withdrawal syndrome and users usually do not develop cravings or seek higher and higher doses. Although humans self-administer LSD, it does not serve as reinforcement in animal models. Nevertheless, because these physiological properties comprise only a couple of criteria for diagnosing a substance use disorder, other criteria (such as use in dangerous situations) are relevant and results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) indicate that the lifetime prevalence of hallucinogen use disorder is 0.6%.

Adverse Effects

Although LSD is considered relatively safe in terms of physical adverse effects when compared with other drugs of abuse, there are case reports of respiratory failure, hyperthermia, and coagulopathies associated with massive doses. In general, there are three main reasons that people who use LSD come to clinical attention: the bad trip, hallucinogen persisting perceptual disorder (HPPD, also known as “flashbacks”), and psychosis.

The Bad Trip

Bad trips occur in about 1 in 10 LSD uses and may lead to an emergency room visit. In addition to the psychological and physiological symptoms described earlier, patients usually have a clear sensorium without memory impairment and are able to provide a complete history. Furthermore, they often are accompanied by someone who was with them when they took the drug and who can confirm the suspected diagnosis.

In some cases a bad trip from LSD may be suspected but a confirmative history cannot be attained. For example, the individual may have unintentionally been exposed, may have been poisoned, or may simply be too agitated to provide a coherent history. Toxicology panels in most acute care settings do not routinely screen for LSD. In these cases, several additional etiologies should be considered such as intoxication with another hallucinogen, psychiatric illness, and delirium.

Differentiating LSD from other phenethylamine and indolealkylamine hallucinogens, for the most part, is academic, as they are treated similarly. It is, however, important to differentiate LSD from phencyclidine (PCP) intoxication because the pharmacological management differs. LSD is not smoked; therefore, if an individual reports having smoked the hallucinogen, PCP should be considered. In addition, individuals intoxicated on PCP are often brought in by authorities because of extremely disorganized, inappropriate, or combative behavior.

Acute LSD intoxication and the bad trip may superficially resemble psychiatric illnesses such as panic disorder, schizophrenia, or the mania of bipolar disorder. Sympathomimetic symptoms, ocular abnormalities (hippos and anisocoria) and visual perceptual disturbances suggest LSD intoxication but are not pathognomonic. Time is commonly the best way to differentiate LSD (substance-induced) psychosis from schizophrenia or mania. Generally, after several hours without pharmacological treatment, LSD intoxication wears off, whereas mania and schizophrenia do not. When substance-induced psychosis is suspected, this may remain a potential diagnosis for up to 4 weeks following last ingestion of the drug. Although feelings of being overwhelmed, scared, and afraid of losing control occur in panic attacks, LSD intoxication is further characterized by dramatic and persistent perceptual distortions. As with any altered mental state, the clinician should have a low threshold for suspecting delirium. Unlike delirium, there is generally no fluctuation in level consciousness with LSD intoxication.

The bad trip generally does not require inpatient hospitalization because of its time-limited course and quick recovery. The patient should be placed in a quiet, nonstimulating environment and provided continuous reassurance that his or her state of mind is drug induced and will not result in permanent brain damage. Given that most emergency rooms are chaotic and understaffed, this may not be a realistic option. Furthermore, the patient may be too disorganized or combative to be talked down. When medications are needed, benzodiazepines are probably the best choice, so long as delirium has been ruled out. The use of neuroleptics should be reserved for instances in which none of the aforementioned efforts have succeeded. High-potency (less-anticholinergic) neuroleptics should be used because anticholinergic neuroleptics have been associated with paradoxical reactions, hypotension, and anticholinergic crises.

Hallucinogen Persisting Perceptual Disorder (HPPD)

Flashbacks are referred to as Hallucinogen Persisting Perception Disorder (HPPD) by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 14 when they cause significant distress. They are defined as “the transient recurrence of disturbances in perception that are reminiscent of those experienced during one or more earlier hallucinogen intoxications.” The most common phenomena are visual distortions such as color confusion, geometric hallucinations, and trailing, but the content of the flashback may involve any of the senses. It is not known what causes flashbacks. Theories include persisting damage to visual processing systems, death of inhibitory cortical interneurons, reverse tolerance, and that they are an atypical dissociative state.

Flashbacks may occur several days to several years after the antecedent use of LSD and have been reported with mescaline, PCP, and cannabinoids. These recurrent visual disturbances, referred to as Hallucinogen Persistent Perceptual Disorder (or HPPD) are roughly divided into Flashback-Type (HPPD I) or HPPD-Type (HPPD II). Flashback-Type visual disturbances are generally pleasant, short-term, reversible, nonintruding, nondistressing, nondisabling, and benign reoccurrences. whereas HPPD-Type visual disturbances are generally unpleasant, long-term, slowly reversible or irreversible, intruding, distressing, disabling, and pervasive reoccurrences. Significant impairment in social, occupational, or other important areas of functioning is usually observed in HPPD II, but not HPPD I.

It is unclear what determines who will experience HPPD and whether or not the experience will be pleasant. These perceptual disturbances have reportedly been induced by a myriad of situations including stress, exercise, pregnancy, sexual intercourse, dark environments, flashing lights, monotony, and use of other psychoactive drugs. Individuals with HPPD II were found to initiate LSD use at an earlier age and report a higher number of overall incidents of use compared to those with HPPD I. Significant differences were found in the type of perceptual disorders between the two types of HPPD. Individuals with HPPD II more commonly report intentionally triggering perceptual disturbances and individuals with HPPD I more commonly report experiencing perceptual disorders triggered by sexual intercourse, dark environment, and looking at still or moving objects.

People experiencing HPPD may seek treatment with their general physician, ophthalmologists, neurologists, or psychiatrists with concerns about their vision, that they have a neurological disorder, or that they are losing their mind. There is no established pharmacological treatment, but case reports suggest that such individuals may respond to typical antipsychotics, clonidine, benzodiazepines, naltrexone, or phenytoin. The antipsychotic risperidone may exacerbate HPPD. In addition, there have been reports of both exacerbation and reduction of HPPD following treatment with selective serotonin reuptake inhibitors. Despite their efficacy and minimal side effects, benzodiazepines may not be the first-line treatment for many individuals with HPPD because of abuse potential.


There have been a significant number of studies that have investigated LSD-induced psychosis and schizophrenia-like symptoms induced by LSD. In animal models, acute injection of the drug induced psychotic behaviors that were classified into positive symptoms, whereas chronic administration of LSD elicited positive symptoms as well as negative symptoms. In humans, administration of LSD to healthy subjects results in an increase in positive schizophrenia-like symptoms. On a population-based level, a study investigating emergency room visits following drug intoxication reported that among those patients referred to the emergency room following LSD ingestion, over 20% were found to have psychotic symptoms. Although this does not reflect the prevalence of psychosis among users of LSD, these rates are higher than those found for cannabinoids, amphetamine, and additional common substances. Given accumulating evidence from preclinical, clinical, and population-based studies, LSD-induced psychosis is a serious concern, although specific data regarding rates of incidence among users are still lacking.


Psilocybin, like LSD, is an indolealkylamine hallucinogen. Psilocybin can be derived from several genera of mushrooms—thus the street name “magic mushrooms.” Psilocybe cubensis is the most common source of psilocybin. This mushroom grows on cow and horse manure in South America, Mexico, and most non-arid areas of the United States. As with LSD, it was Albert Hoffman who isolated and then synthesized psilocybin. It was marketed by Sandoz laboratories under the trade name Indocybin as a potential tool for psychotherapy in the 1960s.

Psilocybin and its active metabolite psilocin are both Schedule I drugs. The spore prints, however, remain legal, presumably to provide mycologists the ability to grow pure psilocybin. Not surprisingly, several drug-oriented magazines advertise home cultivation kits that include live mycelia. The mushrooms can be eaten fresh, dried, or brewed. They are usually ingested orally but there is a case report of intravenous injection. Psilocybin is metabolized into psilocin, which is responsible for the psychoactive effects. Typical doses of psilocybin range from 4–20 mg (40 μg/kg) corresponding to 1–2 g of dried mushrooms. Sympathomimetic symptoms occur at lower doses (3–5 mg), and psychological effects are elicited by doses above 8 mg. Psychological effects begin within 30 minutes of ingestion, peak at 2–3 hours, and dissipate by 12 hours.

Physiological changes are less pronounced than with LSD and are composed mainly of mydriasis and slight elevation in blood pressure and heart rate. The psychological experience is similar to that with other indolealkylamine and phenethylamine hallucinogens, and cross-tolerance develops rapidly. Some users report a more spiritual experience with psilocybin, but this may stem from its well-known use historically in spiritual ceremonies. Griffiths et al. conducted a double-blind controlled study in which hallucinogen-naïve subjects were given either psilocybin or amphetamine under conditions that would foster a spiritual experience. In this study, psilocybin occasioned sustained experiences similar to spontaneously occurring mystical experiences.

In recent years there is a growing body of preclinical and clinical research into the physiological and psychological effects of psilocybin. An imaging study (on healthy humans receiving two doses of psilocybin—0.160 mg/kg and 0.215 mg/kg) showed increased perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula, and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Potential therapeutic effects being explored include substance use disorders, depression, and anxiety. Only one-third of magic mushrooms bought on the street actually contain psilocybin (many are simply store-bought mushrooms laced with PCP) and there are many wild poisonous mushrooms. Adulteration and misidentification seem to be a common cause of serious adverse outcomes.


The indole alkaloid ibogaine is the most abundant hallucinogenic constituent present in the root bark of the West African rainforest shrub Tabernanthe iboga . Extracts derived from this plant have a long history of traditional medicinal and ceremonial use by local people. Ibogaine has been used as an experimental treatment for drug dependence since the 1960s, particularly for cocaine and heroin dependence, and recently clinical studies are emerging indicating that indeed it may be effective. The mechanism of action of ibogaine is unclear, and most probably includes several neurological receptors and transporters, including the sigma-2, kappa- and mu-opioid, serotonergic (5HT2 and 5HT3) receptors, α3β4 nicotinic receptors, and the N -methyl- d -aspartate (NMDA) ion channel.

Despite evidence indicating the efficacy of ibogaine in treating substance use disorders, there are several concerns regarding its toxicity. Nausea and tremors have been reported following oral doses of ibogaine at 500, 600, and 800 mg. In addition to these adverse effects, vomiting, and ataxia are common symptoms following ibogaine ingestion. Although these symptoms may resolve without further adverse effects, in other cases they herald the onset of more severe and, sometimes, life-threating clinical effects. These can include coma, seizures, respiratory difficulties, cardiac arrhythmias, and pulmonary aspiration.

Because ibogaine is achieving widespread popularity for both recreational use as well as an alternate therapy for substance use disorders, there remains insufficient data regarding its efficacy and toxicity. Although a maximal oral dosage of 1 mg/kg has been suggested, using appropriate clinical trials to establish evidence of efficacy, and more importantly establish safe dose, are critical to prevent unnecessary deaths in individuals seeking treatment for substance use disorders.

Phenethylamine Hallucinogens


Mescaline (3,4,5-trimethoxyphenylethylamine), is a phenethylamine hallucinogen naturally found in several species of North and South American cacti. These cacti have been dubbed the “Divine Cacti” in reference to their several thousand year history of spiritual use by natives of Northern Mexico and the Southwestern United States. The North American peyote cactus, Lophophora williamsii , is a small, spineless cactus that grows in the Rio Grande and in parts of the Mexican plateau.

Mescaline was first isolated from peyote cacti in 1896 and was synthesized approximately 20 years later. It is extracted from the head (top) of the cactus, which must be carefully cut at ground level to allow regrowth. Improper harvesting will kill the plant. Because of improper harvesting in Southern Texas, peyote is now listed as an endangered species. Peyote, like the other serotonergic hallucinogens is a Schedule I compound. However, many states allow “bona fide religious” use by members of the Native American Church.

Natural peyote has a bitter taste. It is dried and chewed, soaked in water, and drunk or injected. Mescaline is typically sold as disk-shaped “buttons” composed of either crushed peyote or synthetic mescaline. Genuine peyote is rare outside of the southwestern United States, with less than 17% of street samples actually containing mescaline. The hallucinogenic dose is approximately 5 mg/kg (0.3–0.5 g). Each button contains about 50–100 mg of mescaline, and users typically ingest 3–8 buttons.

Mescaline is markedly less tolerable than the other serotonergic hallucinogens. Within the first 30 minutes, before the onset of psychological symptoms, users experience nausea, vomiting, restlessness, and headaches. By 1–2 hours, however, these unpleasant physiological symptoms dissipate, and the psychic phase characterized by euphoria, sensory distortions, and feelings of confidence begins. The entire experience lasts up to 14 hours. Treatment of acute intoxication and adverse consequences, as with LSD and psilocybin, involves reassurance (talking down) and use of benzodiazepines, if necessary.

3,4-Methylenedioxymethamphetamine (MDMA)

3,4-Methylenedioxymethamphetamine (MDMA/Ecstasy) is a synthetic drug that differs from traditional indolealkylamine and phenethylamine serotonergic hallucinogens in structure, pharmacology, and psychoactive properties, falling somewhere between amphetamine and mescaline. MDMA was first synthesized in 1912. It was patented as a precursor for a psychotherapeutic agent in 1914, as a cough suppressant in 1956, as a tranquilizer in 1960, and as an appetite suppressant in 1961, but it was never marketed. In the early 1980s, MDMA was used in psychotherapy and was purported to improve self-esteem and therapeutic communication. In 1985 the US Drug Enforcement Administration classified MDMA as a Schedule I drug. The United Nations Office on Drugs and Crime Report from 2015 indicates that up to 9,340,000 people globally reported use within the past year. Its use seems to be on the decline in the Americas, where MDMA seizures dropped by 81% between 2009 and 2012. The largest Ecstasy markets are currently East and Southeast Asia and Oceania.


Although MDMA promotes the release and inhibits the breakdown of all monoamine neurotransmitters (serotonin, dopamine, and norepinephrine), its most potent and probably most psychologically important interactions are with the serotonin system. In addition to releasing serotonin and inhibiting its breakdown by monoamine oxidase, MDMA blocks serotonin reuptake by the serotonin transporter. In total, these actions lead to an acute increase of monoamines in the synaptic cleft followed by neuronal completion within 4–6 hours. This depletion is exacerbated by its acute inhibition of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin. The rank order of potency for stimulating monoamine release is norepinephrine = serotonin > dopamine. It is hypothesized that the psychological effects result from MDMA’s effects on the serotonin system, while its physiological effects are adrenergically mediated.

In addition to these amphetamine-like effects, MDMA has affinity for 5HT2, M1-muscarinic, H1-histaminergic, and α2-adrenergic receptors, but the clinical significance of this receptor-binding profile is unclear. MDMA also indirectly raises blood levels of adrenocorticotropin-releasing hormone, antidiuretic hormone, cortisol, dehydroepiandrosterone, oxytocin, and prolactin. Oxytocin and prolactin are naturally released following orgasm and childbirth and are thought to facilitate bonding. It has been hypothesized that MDMA-mediated release of these hormones results in the sense of intimacy central to the MDMA experience.

MDMA is hepatically metabolized via the cytochrome P450 (CYP) system. It has saturable kinetics, meaning that at higher doses metabolism is slower and toxicity is disproportionably more likely. So far, identified metabolites include 3,4-methylenedioxyamphetamine, 4-hydroxy-3-methoxy-methamphetamine, 4-hydroxy-3-methoxyamphetamine, 3,4-dihydroxyamphetamine (also called alpha-methyldopamine), 3,4-methylenedioxyphenylacetone, and N -hydroxy-3,4-methylenedioxyamphetamine. The contribution of these metabolites to the psychoactive and toxic effects of MDMA is an area of active research.

3,4-Methylenedioxyamphetamine is known to be psychoactive and like MDMA it causes release of serotonin and produces an empathogenic experience. It also resembles the traditional serotonergic hallucinogens in that it has higher affinity for the 5HT2A receptor and produces more profound sensory disturbances. Much of the toxicity associated with MDMA has been attributed to this metabolite. In addition to being a metabolite of MDMA, 3,4-methylenedioxyamphetamine has been synthesized and is used recreationally under the name MDA, or “Mellow Drug of America.”

Street Information

MDMA is universally referred to as Ecstasy, but its street names include “XTC,” “X,” “E,” “M,” “Rolls,” “Beans,” “Disco Biscuit,” “Adam,” “Clarity,” “Lovers speed,” and “Hug Drug.” The practices of combining MDMA with LSD or psilocybin to produce a more powerful psychological experience are referred to as “Candy Flipping” and “Hippie Flipping,” respectively. Mentholated products such as cigarettes or vapor rub are often used to heighten the drug’s effects.

MDMA is distributed as small single-dose tablets of various colors often decorated with icons or phrases ( Fig. 31.3 ). These tablets usually contain 15–150 mg of MDMA. The tablet form lends a pharmaceutical appearance and a false impression that the contents are safe and uncontaminated. However, pure MDMA, as described below, is considerably less safe than perceived by most users, and often the contents are contaminated with acetaminophen, stimulants, or other hallucinogens. Although MDMA is usually ingested orally, the tablets can be either crushed and snorted or dissolved and injected.

Jan 19, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Serotonergic Hallucinogens
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