Hallucinogens: Chapter 12

Hallucinogens

Definition and Classification

• Hallucinogens: A broad term referring to drugs that produce an “altered state of consciousness,” affecting sensory perception, mood, thinking, and physiological processes.

• Alternative Terminology:

  • Psychomimetics: Means their effects mimic psychotic symptoms (e.g., schizophrenia).

  • Psychedelics: From the 1960s, meaning “mind-expanding or mind-revealing”; there is controversy over whether this is appropriately descriptive.

• Hallucinogens can originate from over 90 different species of plants and numerous synthetic agents.

Types of Hallucinogens Based on Mechanisms of Action

• Serotonergic Hallucinogens:

  • Produce visual hallucinations.

  • Examples: LSD, mescaline, psilocybin.

• Methylated Amphetamines:

  • Alter mood/consciousness with relatively few sensory changes.

  • Examples: MDA and MDMA (Ecstasy/Molly).

• Anticholinergic Hallucinogens:

  • Lead to a trancelike state with little response to external stimuli and reduced memory.

  • Examples: Atropine and scopolamine.

• Dissociative Anesthetics:

  • Suppress sensation and anxiety without necessarily causing loss of consciousness.

  • Examples: PCP (angel dust) and ketamine.

• Salvinorin A:

  • Alters visual and auditory perception.

  • Source: Salvia divinorum, a plant in the sage family.

Early History of Hallucinogens

• Documentation by Fernando Hernandez (1577):

  • Studied plants used by Aztecs, including Peyote cactus (mescaline), Psilocybe mushrooms (psilocybin to psilocin), and morning glory seeds (lysergic acid amide).

  • Aztecs regarded these hallucinations as prophetic, assisting in decision-making and healing rituals.

• Spanish Account (1500s): Describes Aztecs’ reactions to mushroom-induced intoxication:

  • Experience of visions provoking varied emotions; examples include visions of death, wild beasts, and fortunes.

Ayahuasca

• Composition and Use: A tea used traditionally by indigenous peoples across South America, containing DMT (dimethyltryptamine) and a MAO inhibitor from a woody vine, allowing DMT's psychoactive effects to last longer (1-2 hours).

• Primarily used in healing ceremonies and initiation rites.

Recent History and the Psychedelic Movement

• 1960s: First major impact of hallucinogens on mainstream culture due to the psychedelic movement:

  • 1938: Albert Hofmann synthesizes LSD.

  • 1943: Hofmann experiences hallucinations after deliberate exposure.

• By the early 1960s, LSD's popularity surged, promoted by figures like Harvard psychologist Timothy Leary and author Ken Kesey, as well as music groups associated with the LSD culture (e.g., Grateful Dead).

• Decline: Late 1960s witnessed increasing negative publicity around LSD, leading to declines in usage through the 1970s and 1980s, but a resurgence in the 1990s. Interest in other hallucinogens like DMT and psilocybin is growing.

Mechanisms of Action of LSD-Like Drugs

• Chemical Structure: The structures of LSD, psilocybin, and related hallucinogens resemble the neurotransmitter serotonin.

• Receptor Activity:

  • LSD, psilocybin (to psilocin), and mescaline act as agonists for the 5-HT2A subtype of serotonin receptors, which are G-protein-coupled and excitatory.

Pharmacokinetics of LSD-Like Drugs

• LSD:

  • Highly potent, with effects observed at doses as low as 25 micrograms.

  • Subjective effects typically noted within 20-60 minutes, persisting for 8-12 hours.

  • Rapidly metabolized with detection limits in urine up to 72 hours post-use.

• Psilocybin: Duration of action is approximately 4-6 hours.

• Mescaline: Duration ranges from 10-14 hours.

• DMT: Effects last only around 1 hour, with variability in dosing due to administration methods.

Psychotherapeutic Uses and Research

• Historically viewed two-fold: Therapists might benefit from experiencing psychotic-like symptoms during treatment.

  • Discarded notion: LSD hallucinations primarily visual, unlike auditory hallucinations common in schizophrenia.

• Antipsychotics like chlorpromazine are effective antagonists of LSD effects, highlighting biochemical insights in mental disorders.

• Hallucinogens are being researched for therapeutic potential:

  • Promising results for psilocybin in treating anxiety, depression, drug dependence, and MDMA for PTSD.

Physiological and Psychological Effects of Serotonergic Hallucinogens

• Physiological Effects:

  • Pupil dilation, sweating, increased heart rate, elevated blood pressure, increased body temperature.

• Psychological Effects:

  • Highly variable experiences among individuals, including profound visual perception changes such as:

  • Form Constants: Spiral explosions, vortex patterns, lattice patterns.

  • Synesthesia: Experiencing mixed sensory modalities (e.g., “seeing” music).

  • Visual alterations: Increased brightness and saturation, motion perception in stable objects.

• Adverse Effects:

  • Potential for acute panic reactions or “bad trips” which can lead to acute psychotic states.

  • Flashbacks diagnosed as hallucinogen persisting perception disorder can occur if severe.

Methylated Amphetamines (e.g., MDMA)

• Effects: Similar profiles for MDMA, MDA, and MDE:

  • Absorbed rapidly; duration approximately 6-8 hours ahead of serotonin release.

  • Initial increase in serotonin followed by a marked decrease in activity.

  • Sympathomimetic effects include increased heart rate and body temperature.

  • Psychological effects involve euphoria, emotional warmth, and lowered defensiveness.

  • Setting and social dynamics amplify effects.

• Toxicity: High-risk reactions can lead to dehydration, heat-related illnesses, and fatal outcomes; often linked to high-energy settings.

  • Common adulterants complicate safety, including bath salts and methamphetamine.

Residual Effects of MDMA

• Neurotoxic effects demonstrated in animal studies indicate potential long-term impacts on serotonergic neurons.

  • Effects can be more significant with binge usage patterns (multiple doses in one evening).

• Reports of mood, memory, and attention deficits; recovery rates of neurons are debated.

Psychotherapeutic Uses of Methylated Amphetamines

• Advocated for MDMA's role in enhancing communication and empathy in therapy.

• Emerging controlled trials support its use as an adjunct for PTSD treatment.

Anticholinergic Hallucinogens

• Mechanism of Action: Atropine and scopolamine block acetylcholine receptors in the brain.

• Physiological Effects: Include dry mouth, blurred vision, increased heart rate, and potential respiratory failure at high doses.

• Historical Use: Known as witches' brews in ancient practices, including deadly plants like belladonna and mandrake used for their hallucinogenic properties.

Dissociative Anesthetic Hallucinogens

• Drugs Included: PCP and ketamine; PCP became prevalent as a street drug in the 1970s.

• Mechanism of Action: Interferes with excitatory neurotransmission, particularly at NMDA receptors.

• Effects: May produce feelings of euphoria, numbness, or catatonia; overdose potential includes respiratory failure and prolonged psychotic states.

Salvinorin A (Salvia)

• Source: Salvia divinorum, traditionally used by the Mazatec people for sacred rituals; inhalation or oral ingestion leads to intense experiences lasting less than 30 minutes.

• Effects: Can induce trance states with visual hallucinations; noted for highly variable emotional responses ranging from pleasure to anxiety.

• Mechanism of Action: Functions as an agonist at kappa opioid receptors.

Hallucinogens: Comprehensive Overview

Origin, Source, and Production

• Hallucinogens originate from over 90 different species of plants and numerous synthetic agents.

• Early documented sources (Fernando Hernandez, 1577) included:

  • Peyote cactus (source of mescaline).

  • Psilocybe mushrooms (contain psilocybin).

  • Morning glory seeds (contain lysergic acid amide).

• Ayahuasca: A tea from indigenous South America, combining DMT (dimethyltryptamine) and an MAO inhibitor from a woody vine.

• LSD: Synthesized by Albert Hofmann in 1938.

• Salvinorin A: Sourced from Salvia divinorum, a plant in the sage family.

Uses and Benefits

• Historical Uses:

  • Aztecs used Peyote, Psilocybe mushrooms, and morning glory seeds for prophetic visions, assisting in decision-making and healing rituals.

  • Ayahuasca is primarily used in healing ceremonies and initiation rites by indigenous peoples.

  • Anticholinergic hallucinogens (e.g., belladonna, mandrake) were historically used in ancient 'witches' brews' for their hallucinogenic properties.

  • Mazatec people traditionally used Salvia divinorum for sacred rituals.

• Psychotherapeutic Research:

  • Psilocybin shows promising results in treating anxiety, depression, and drug dependence.

  • MDMA is being researched as an adjunct for PTSD treatment, advocating for its role in enhancing communication and empathy in therapy.

Relevant Routes of Administration

• DMT: Varies due to administration methods.

• MDMA: Absorbed rapidly, typically orally as pills.

• Salvinorin A (Salvia): Inhalation or oral ingestion.

Mechanism of Action

• Serotonergic Hallucinogens (LSD, psilocybin, mescaline):

  • Resemble serotonin chemically.

  • Act as agonists for the $5-HT_{2A}$ subtype of serotonin receptors, which are G-protein-coupled and excitatory.

• Methylated Amphetamines (MDMA, MDA, MDE):

  • Cause an initial increase in serotonin followed by a marked decrease in activity.

• Anticholinergic Hallucinogens (Atropine, scopolamine):

  • Block acetylcholine receptors in the brain.

• Dissociative Anesthetics (PCP, ketamine):

  • Interfere with excitatory neurotransmission, particularly at NMDA receptors.

• Salvinorin A:

  • Functions as an agonist at kappa opioid receptors.

Pharmacokinetics

• LSD:

  • Highly potent, with effects at doses as low as $25$ micrograms.

  • Subjective effects noted within $20-60$ minutes, persisting for $8-12$ hours.

  • Rapidly metabolized, detectable in urine up to $72$ hours post-use.

• Psilocybin:

  • Duration of action: approximately $4-6$ hours.

• Mescaline:

  • Duration: $10-14$ hours.

• DMT:

  • Effects last only around $1$ hour, with variability in dosing.

• MDMA, MDA, MDE:

  • Absorbed rapidly; duration of effects approximately $6-8$ hours.

Acute and Chronic Effects

• Serotonergic Hallucinogens:

  • Physiological: Pupil dilation, sweating, increased heart rate, elevated blood pressure, increased body temperature.

  • Psychological: Profound visual perception changes (form constants, synesthesia, increased brightness/saturation), acute panic reactions ('bad trips'), acute psychotic states.

  • Chronic (Adverse): Flashbacks, potentially diagnosed as hallucinogen persisting perception disorder.

• Methylated Amphetamines (MDMA):

  • Acute: Euphoria, emotional warmth, lowered defensiveness, sympathomimetic effects (increased heart rate and body temperature).

  • Toxicity (Acute): Dehydration, heat-related illnesses, fatal outcomes, often linked to high-energy settings and adulterants.

  • Chronic: Neurotoxic effects on serotonergic neurons (more significant with binge usage), reports of mood, memory, and attention deficits.

• Anticholinergic Hallucinogens:

  • Physiological: Dry mouth, blurred vision, increased heart rate, potential respiratory failure at high doses.

  • Psychological: Trancelike state with little response to external stimuli, reduced memory.

• Dissociative Anesthetic Hallucinogens:

  • Psychological/Physiological: Euphoria, numbness, catatonia, overdose potential includes respiratory failure and prolonged psychotic states.

• Salvinorin A (Salvia):

  • Psychological: Intense experiences lasting less than $30$ minutes, trance states with visual hallucinations, highly variable emotional responses (pleasure to anxiety).

Tolerance and Dependence

• The note indicates that psilocybin is being researched for treating drug dependence, suggesting traditional serotonergic hallucinogens might not induce high levels of physical dependence.

• While not explicitly stating tolerance, the mention of