Early History (1 of 2)

Spanish conquistadores encountered civilizations in Mexico and Central and South America that used hallucinogenic plants in religious ceremonies

Early documentation by Fernando Hernandez, royal physician to king of Spain, who studied plants the Aztecs used in 1577

Peyote cactus (peyotl)

Psilocybe mushrooms (teonanacatl)

Morning glory seeds (ololiuqui)

These all contain different drugs, but all produce vivid visual hallucinations

Aztecs saw these hallucinations as oracles that could reveal the future, solve mysteries, aid decision-making, and help shamans heal the sick

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Early History (2 of 2)

Aztecs in northern Mexico and southwestern Texas used peyote cactus

In the 18th and 19th centuries, the peyote religion spread to Native Americans in western Mexico and throughout the United States

Aztecs and Mayans viewed psilocybin mushrooms as sacred

South America: Ayahuasca

Used by indigenous peoples in Brazil, Colombia, Peru, Ecuador, and Bolivia

Includes dimethyltryptamine = DMT, found in many plants in this Amazon region

Virola tree, Chacruna bush

Also includes a woody vine whose MAO inhibitor prevents DMT breakdown

Produces a 1- to 2-hour experience with intense visual hallucinations

Traditionally used in healing ceremonies, initiation rites, and other rituals

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Recent History (1 of 2)

Despite their long history of use, hallucinogenic drugs had no impact on mainstream European or American culture until the 1960s, when their use exploded

History of “psychedelic movement”: 1938—Basel, Switzerland

Chemist Albert Hofmann at Sandoz Laboratories discovered lysergic acid diethylamide (LSD) while studying the fungus ergot, whose derivatives have medical uses

Hofmann synthesized compounds, one of which was LSD

1943: Hofmann was the first to experience hallucinations after first accidental and then deliberate experimental exposure to LSD

Sandoz offered LSD to psychiatrists and psychologists for use to aid in psychotherapy

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Recent History (2 of 2)

By the early 1960s, many people had tried LSD, and it gained publicity

Harvard psychologist Timothy Leary, Ram Dass (Richard Alpert), and author Ken Kesey all popularized LSD use

Music of groups like the Grateful Dead, Jefferson Airplane, Jimi Hendrix, became known as “acid rock”; eventually the Beatles joined the movement

By the late 1960s, LSD was the most controversial drug in the world

Thought to cause chromosomal damage, mental illness, suicide, homicide, violence

Loss of faith in LSD as a source of spiritual enlightenment

LSD use declined in 1970s and throughout 1980s, increased again in 1990s, then declined again

Interest in related hallucinogens DMT and psilocybin seems to be rising

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Mechanisms of Action of LSD-Like Drugs

Chemical structures of LSD, psilocybin, and other major hallucinogens resemble that of the naturally occurring neurotransmitter serotonin

Considerable support for hypothesis that these drugs mimic serotonin and thus activate serotonin receptors in the brain

LSD and related drugs bind to the 5-HT2A subtype of serotonin receptors

Mescaline has a chemical structure more like amphetamines than LSD, and it affects both noradrenergic and serotonergic systems

However, mescaline produces hallucinations virtually identical to those of LSD

Further evidence for a common mechanism of action:

Tolerance to the effects of both LSD and mescaline develops rapidly

Cross-tolerance between LSD, mescaline, and other drugs of this class

Serotonin is widely distributed in the brain

May account for varied effects of LSD-like hallucinogens and effects on mood and emotions

Research finds LSD increases communication among brain regions with high density of

5-HT2A receptors

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Pharmacokinetics of LSD-Like Drugs

LSD:

Rapidly absorbed; subjective effects usually noted within 20–60 minutes

Distributed throughout the body; readily penetrates blood-brain barrier

Effects persist 8–12 hours

Rapidly metabolized and eliminated from the body

LSD or its metabolites cannot be detected in urine for more than 72 hours after use

Psilocybin:

Duration of action is c. 4–6 hours

Mescaline:

About 1/3,000 as potent as LSD

Duration of action is c. 10–14 hours

DMT:

Duration of action is only c. 1 hour

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Psychotherapeutic Uses

Historically, LSD and related drugs have been thought to have two applications:

The idea that LSD produced psychotic symptoms, so therapists would benefit from having experiences like those of their patients

This idea has been discarded

Differences: LSD hallucinations are mainly visual, whereas schizophrenic hallucinations are usually auditory, so subjective experiences are not the same

Similarity: Antipsychotics like chlorpromazine, used to treat schizophrenia, are also effective antagonists of LSD effects, so may provide clues about biochemistry of mental disorders

The use of hallucinogens as an adjunct to psychotherapy

Based on the idea that therapists could learn important information from patients using LSD, and patients could gain insight into their condition, because LSD could break down ego defenses

Recent research finds promising results of psilocybin for treating anxiety, depression, drug dependence; MDMA for PTSD; and ketamine for depression

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Effects of Serotonergic Hallucinogens (1 of 2)

Physiological effects of LSD and related drugs are akin to those of amphetamine and cocaine

Sympathomimetic effects, including pupil dilation, sweating, and increased heart rate, blood pressure, and body temperature

Psychological effects are harder to describe, as experiences are highly variable among individuals, and may also vary among experiences for one individual

Common to all serotonergic hallucinogens: Profound changes in visual perception

Some consistency in the types of visual changes

Form constants = Spiral explosions, vortex patterns, the lattice pattern

Synesthesia—experiencing a stimulus in a different sensory modality than the one in which it was presented (“seeing” music, “hearing” colors, etc.)

Flashing lights, increased brightness and saturation of colors, trails or plumes around objects, the sense of movement in stable objects, visual patterns seen as in motion

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

The Spiral Explosion Form Constant

An artist’s rendition of the spiral explosion form constant.

Overview: Methylated Amphetamines

MDMA rapidly increased in popularity during the late 1990s

Use by high school seniors doubled from 1996 to 2001

From 4.6% to 9.2%

Use declined thereafter, to a low of 2.7% in 2016, then leveled off

Publicity about many adverse effects, including brain damage and death, is one important reason for this decline

As better understanding of MDMA has developed, research into its potential therapeutic benefits has resumed

MDA, MDMA, and MDE produce few or no visual hallucinations; main effects are mild euphoria, along with openness, feelings of warmth and empathy, and lack of defensiveness

These properties led some psychotherapists to advocate the use of these drugs as an adjunct to therapy

Some scientists classify MDMA with hallucinogens, others with amphetamines, and others in a unique category as entactogens or empathogens because of their psychological effects

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

History and Epidemiology

Methylated amphetamines were developed in the early 1900s, but got little attention until the late 1960s

DOM and MDA were used during this time

Use of MDA and LSD declined in the 1970s, while MDMA increased in popularity

Publicity about MDMA’s therapeutic benefits, plus its nickname “Ecstasy” and reputation as the “love drug” made it attractive

MDMA or Ecstasy was a legal drug until 1985

Based on its explosive rise in use, plus animal research suggesting brain damage, the DEA classified MDMA as Schedule I in 1985

Popularity of MDMA grew through the “club” or “rave” subcultures

Raves declined in the late 1990s, but have increased in recent years

MDMA became the fastest-growing illegal drug across the United States, Western Europe, and Australia by the early 2000s, and remains a popular recreational drug today

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Ecstasy

MDMA (Ecstasy) was the prototypical club drug.

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Effects of Methylated Amphetamines

The effects of MDMA, MDA, and MDE are very similar

Absorbed rapidly; duration of action c. 6–8 hours

Neural mechanisms:

Release of monoamines, particularly serotonin

MDMA also blocks reuptake of serotonin and, to a lesser extent, dopamine

Initial overall increase in serotonin and dopamine activity

After several hours, followed by a marked decrease in serotonin activity

Sympathomimetic effects: Increased heart rate, blood pressure, body temperature, pupil dilation, muscle tension, bruxism (teeth-grinding), appetite suppression, insomnia—much like amphetamine effects

Psychological effects: Euphoria, increased emotional warmth and empathy, lowered defensiveness, increased verbal behavior

Characteristics of club or rave settings amplify the psychological effects

While MDMA’s effects profile is much like that of amphetamine, research participants have consistently reported a preference for MDMA

Research studies suggest MDMA has unique effects that enhance emotional and empathetic responses in social situations

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Toxicity

Use of MDMA has been associated with reports of toxic reactions and deaths

Toxic reactions include dehydration, heatstroke, heat exhaustion, muscle breakdown, kidney failure, stroke, seizures, and heart attacks

Toxic effects are often related to elevated body temperature: May be compounded by intense physical activity and high temperatures in many clubs

Some emergency cases have involved collapse due to low sodium levels

Complication: Adulterants are very common in street MDMA

Common adulterants found in sample analyses include bath salts, methamphetamine, caffeine, methadone, 2C-I-NBOMe

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Residual Effects of MDMA (1 of 2)

One major controversy: Possibility of long-term damage to certain brain structures

Neurotoxic effects like degeneration of serotonergic neuron terminals, causing serotonin depletion, have been found in rats and primates

Criticism: Doses used in animal studies are higher than usual street doses

Hard to evaluate this, as doses in street MDMA tablets vary enormously

Many users take multiple doses in one evening, which could be neurotoxic

Neuron recovery rates are also debatable; however, one study in nonhuman primates found effects persisting for as long as 7 years after drug administration

PET scans have found reduced serotonergic functioning after heavy MDMA use

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Residual Effects of MDMA (2 of 2)

There is also evidence that the serotonin system recovers after a period of abstinence

Functional significance of neural changes also has been controversial

Adulteration of MDMA, plus use of other drugs, psychopathology, and other individual differences are all confounding variables

It remains to be seen what long-term effects may be associated with MDMA use

MDMA has not been determined to be safe

However, low doses, given under controlled conditions, are recognized not to cause neurotoxicity

This has revived interest in its use as an adjunct to psychotherapy

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Psychotherapeutic uses of Methylated Amphetamines

Some therapists advocated use of MDMA because it seems to enhance communicative ability and empathy and decrease defensiveness

Because MDMA does not cause hallucinations or dissociation like LSD, it was seen as less likely to produce adverse reactions

Small-scale controlled trials in recent years have given some support for the value of using MDMA as an adjunct to therapeutic treatment of posttraumatic stress syndrome (PTSD)

One research team (Mithoefer et al., 2011, 2013) found therapeutic benefits that remained 2 years following treatment

Another research team (Oehen et al., 2013) found similar benefits for clients with MDMA-assisted therapy vs. those receiving an active placebo control

More research is needed to determine safety and efficacy

Several ongoing Phase 2 studies of MDMA are currently being conducted, which may yield answers

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Knowledge Check 2: Methylated Amphetamines

Question: Some research trials have found that MDMA or Ecstasy provided therapeutic benefits during psychotherapy sessions for clients who have:

posttraumatic stress disorder.

generalized anxiety disorder.

a major depressive disorder.

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Knowledge Check 2: Answer

Question: Some research trials have found that MDMA or Ecstasy provided therapeutic benefits during psychotherapy sessions for clients who have:

posttraumatic stress disorder.

generalized anxiety disorder.

a major depressive disorder.

Answer: a. posttraumatic stress disorder (PTSD). Several controlled trials have found that in psychotherapy sessions, MDMA enabled clients with posttraumatic stress to talk more easily about events that would otherwise be too anxiety-producing for them to discuss. No research is cited in the text regarding any use of MDMA during therapy for generalized anxiety disorder or major depressive disorder.

Maisto, Drug Use and Misuse, 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Anticholinergic Hallucinogens

12.4

Maisto, Drug Use and Misuse], 9th Edition. © 2022 Cengage. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Anticholinergic Hallucinogenic Drugs

Atropine and scopolamine block acetylcholine receptors in the brain

At low doses, these are used for various medical purposes

Atropine, being an acetylcholine antagonist, is an antidote to the deadly nerve gases sarin and soman, which otherwise inhibit the enzyme that breaks down acetylcholine

These drugs can also produce hallucinogenic effects

Ancient Greeks used plants containing them

Medieval “witches’ brews” included plants like belladonna (deadly nightshade), mandrake, henbane,

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