Ch 12 TB: Hallucinogens

Hallucinogens

alter the state of consciousness
drugs that radically change the mental state by distorting the perception of reality to the point where hallucinations occur
  * illusionogenic
  * psychotomimetic: mimic psychosis inducing state
  * psychedelic
  * mind expanding
mimic symptoms of functional psychoses such as schizophrenia
rare usage today
do not fit in the same category
the effects of hallucinogens differ from natural psychosis
psychedelic: mind expanding or mind revealing
affect mood, thinking processes, and physiological processes
alter nearly all aspects of psychological functioning
==four subgroups of hallucinogens==: serotonergic hallucinogens, methylated amphetamines, anticholinergic hallucinogens, and dissociative anesthetics
==delusions==: thought process/belief that did not exist

Serotonergic Hallucinogens

Class of drugs that includes ==LSD== and drugs with similar effects and mechanisms of actions
==mescaline (peyote cactus)==
* Peyote= most widespread hallucinogenic drug in the New World
==psilocybin== (from certain mushrooms)
produce vivid visual hallucinations + variety of effects on consciousness
have differing chemical structures, but all drugs influence serotonergic transmission in the brain
Activation of 5HT 2A receptor is a key factor in producing visual hallucinations

Methylated Amphetamines

Includes MDA and MDMA (ecstasy)
structurally related to amphetamine
produce alterations in mood and consciousness with little or no sensory change
act on DA, norepinephrine, and 5HT synapses
effects are most potent on the serotonergic system
do not bind selectively to the 5-HT 2A receptor

Anticholinergic Hallucinogens

Class of drugs including atropine and scopolamine found in plants such as mandrake, henbane, belladonna, and jimsonweed
produce dreamlike trances, awaken with little or no memory of the experience
antagonists

Dissociative Anesthetics

class of drugs including PCP (angel dust) and ketamine
produces surgical anesthesia while individuals remains at least semiconscious

Salvia divinorum (salvinorin A)

most widely used hallucinogens
chemical found in a plant in the sage family
not a federal controlled substance, but some states have banned it
acts differently on the brain when compared to other hallucinogens
affects kappa receptors, classified as the kappa hallucinogen

Serotonergic Hallucinogens: LSD and Related Compounds

Early History

Spanish conquistadores explored and colonized Mexico and other parts of Central and S America
used for religious/ritualistic practices; mind expansion, vision, prophecy
plants produced vivid visual hallucinations
Indigenous people took visions as oracles that could reveal the future and aid in decision making
mushrooms were viewed as sacred
still used in Mexico today

Recent History

drugs had no impact on mainstream European or American culture until 1960s
{{Psychedelic movement{{
  * Basel Switzerland; Albert Hofmann discovered LSD in 1938
  * He perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors
  * Normal effective dose: 25 to 125 micrograms; can be as low as 10 micro grams
  * LSD began to be distributed as an adjunct to psychotherapy
  * LSD would break down the patient’s normal ego defenses and facilitate the psychotherapy processes
  * LSD is a psychotomimetic; it is mimicked by psychosis
  * LSD became most controversial drug in the world by the 1960s
  * negative claims about LSD: chromosomal damage, resulting in mutant children, insanity, suicide, acts of violence, and homicidal behavior; led to decline in use in 70s and 80s
  * use increased in 90s, especially among high schoolers
LSD is the most potent, its effects are experienced within 8-12 hours

Serotonin (5HT)

important in regulation of:
* sleep, mood, impulsivity, and cognition
* Found in the brain, blood, and GI tract (and Substantia Nigra)
Produced in the ==raphe nucleus==
* projections sent to nerve endings up to the brain or down to the spinal cord
depletion
* prolonged wakefulness
stimulation of serotonin rich cells
  * analgesia (inability to feel pain)
  * sleepiness
  * changes in appetite

Mechanisms of Action of LSD-Like Drugs

small doses can produce dramatic effects for visual hallucinations and alterations of consciousness remain enigmatic (difficult to understand)
alters activity of the brain systems mediated by 5-HT NT
==partial agonist== at serotonin receptors
chemical structures of major hallucinogens resemble naturally occurring transmitter 5-HT
* compounds mimic natural 5-HT and activate 5-HT receptors in the brain
* LSD elicits behavioral attributes of 5HT 2A receptor
Problem: ==Mescaline’s chemical structure is different from the others==
  * mescaline produces vivid visual hallucinations virtually identical in form to those of LSD
  * Cross tolerance between LSD, mescaline, and other serotonergic hallucinogens
  * mescaline and LSD are agonists at the specialized group of serotonin receptor subtypes, 5-HT 2A
Many drugs that affect serotonin do NOT produce hallucinations
* BUT HOW CAN SEROTONERGIC HALLUCINOGENS PRODUCE REMARKABLE EFFECTS ON VISUAL EXPERIENCE?!?!?!?!?!?!?

Pharmacokinetics of LSD-Like Drugs

All hallucinogens that act on 5-HT receptors have similar effects
What do the drugs vary in?
  * potency
    * LSD is the most potent
  * duration of action
  * other pharmacokinetic variables
LSD is rapidly absorbed; subjective effects are noted w/in 20 to 60 mins
LSD is distributed throughout the body and penetrates BBB
Effects persist for 8 to 12 hours then drug is rapidly metabolized and eliminated from the body
Can detect LSD and metabolites in urine for 72 hours after use
DMT: dimethyltryptamine; relatively short acting
* effects begin w/in minutes, but persist for about 60 minutes
Chloropromazine is an effective antagonist
* reverse effects are seen with LSD

Psychotherapeutic Uses

LSD produced a model psychosis
psychotherapists would benefit from having experiences similar to those of their patients
Visual vs. auditory
  * different sensory systems are impacted
    * hallucinations under LSD influence are visual
    * schizophrenics are usually auditory
    * subjective experience is not identical
Hallucinogens and use as adjunct to psychotherapy
* therapists learn important info when patients use LSD and that patients gain better insight into condition b/c LSD could break down ego defenses
Moderate dose of psilocybin administered to patients w/advanced stage cancer reduced anxiety and depression

Effects of Serotonergic Hallucinogens

{{Physiological effects of LSD{{
  * similar to amphetamine and cocaine
  * they are sympathomimetic
  * pupil dilation
  * increase HR
  * increased BP
  * increased Body Temp, sweating
{{Psychological effects{{
  * difficult to characterize due to subjectivity
  * profound visual perception is common among individuals
    * spiral explosions and vortex patterns
    * lattice pattern: checkerboard pattern that appears on plain surface
    * flashing lights
    * increased brightness and saturation of colors
    * sense of movement in stable objects
    * trails or plumes around objects
  * synesthesia: the experience of sensing a sound stimulus as a visual one
    * subject reports “seeing” music
  * {{other effects:{{
    * mood is labile, easily altered
    * bizarre cognitive experiences occur
    * emotional state varies
    * “magical” and thinking
    * “mystical type” experiences are reported under a high dose

Adverse Effects of Serotonergic Hallucinogens

Controversy about their potential to produce a variety of adverse effects
LSD use produced chromosomal damage
  * individual who had drug would have deformed children
  * THERE IS NO CONVINCING EVIDENCE THAT LSD (OR SEROTONERGIC HALLUCINOGENS) INCREASE BIRTH DEFECTS IN OFFSPRING WHEN TAKEN IN NORMAL DOSES
  * risk of fetal damage if taken by pregnant women
Bad trips: leave individual in acute psychotic state, might harm themselves or others
* Psychological state of the user and environmental setting are important
Flashback: sudden recurrence of an LSD-like experience
  * event occurred months or years before
  * nature of experience:
    * visual disturbances, flashes of color, trails in visual field, fleeting perceptions in peripheral field of view
  * flashbacks are brought on by stress, fatigue, entering dark environment, or MJ use
  * it’s difficult to estimate the frequency of flashbacks
  * Treatment- antipsychotics or benzodiazepines
difficult to determine whether LSD caused psychosis or person was psychotic to begin with and LSD made symptoms more flagrant
* generally involves individuals who had already been diagnosed or have psychotic symptoms before drug use

Methylated Amphetamines

Ecstasy (MDMA) Overview

most controversial illegal drug in society
increase in popularity in late 1990s
declined after 2001
* MDMA claimed to produce brain damage and death
influence 5-HT, DA, and norep. transmission
mild euphoria (excitement, happiness), openness, feelings of warmth and empathy, lack of defensiveness

History and Epidemiology

MDMA patented in 1914 by Merck Pharmaceuticals in Germany
known as the love drug
MDA and MDMA are Schedule 1
rave movement, from Europe to US
MDMA remains one of the most popular recreational drugs
most widely used illegal drug in Europe after MJ

Effects of Methylated Amphetamines

usually taken orally,
but can be injected
or absorbed intranasally (snorted)
rapidly absorbed
duration of action: 6 to 8 hours
MDMA blocks reuptake of 5-HT and DA
Overall: increase in 5-HT and DA activity, several hours later, decrease in 5-HT activity
sympathomimetic effects at effective doses
  * pupil dilation
  * increased HR, BP
  * muscle tension
  * teeth grinding
  * increase Body temp
  * appetite suppression
  * insomnia
effects very similar to amphetamine
stronger reinforcing effects for MDMA than amphetamine at all doses; reported to like MDMA better
physical withdrawal symptoms
  * drowsiness
  * muscle pain
  * depression
  * paranoia
  * anxiety
==MDMA does not produce hallucinations== or the dissociation of LSD, less likely to produce adverse reactions

MDMA Toxicity

dehydration, heatstroke, heat exhaustion, muscle breakdown, kidney failure, stroke, seizures, heart attacks
elevated body temperature
most toxic reactions occur at high doses or when multiple doses have been taken, but death can occur at low doses
encouraged to drink fluids, but excessive fluids intake can alter the salt balance

Residual Effects of MDMA

rats had depletion of serotonin, depletion of serotonergic neuron terminals after many doses of MDA
neurotoxic effects can be produced after a single high dose (20 mg/kg), or with several low doses (5 mg/kg) over consecutive days
doses considered moderate in animal studies are higher than doses generally used on the street
most pills contain an average of 70 to 100 mg MDMA; ==below the dose range that is neurotoxin in humans==
==5-HT modulates sleep, mood, and other functions==; depletion of 5-HT can lead to serious problems
there is a reduction in 5-HT functioning between heavy MDMA users and controls
the 5-HT system can recover from the effects after a period of abstinence
most MDMA users also use other drugs
* heavy MDMA users showed more evidence of psychopathology (particularly depression) than nonusers
MDMA users showed more severe deficits on memory and other cognitive tasks than control participants matched for drug use other than MDMA
Still debating long term effects of MDMA use
* MDMA and related drugs pose risks of acute toxic effects and possible deficits in neuropsychological functioning, particularly among heavy users

Anticholinergic Hallucinogens

Atropine and scopolamine: anticholinergic hallucinogens found in certain plants
Plants: belladonna (deadly nightshade); mandrake, henbane, jimsonweed
* block metabotropic (slow acting) acetylcholine receptors in the brain
* used in “witchcraft”
Physiological effects:
  * dry mouth
  * blurred vision
  * loss of motor control
  * increased HR and Body Temp
  * cause respiratory failure (cessation of breathing) at doses higher than the effective dose
Psychological experience:
  * dreamlike trance or stupor
  * seem delirious and confused
  * can describe their visions if asked
  * memory of the drug experience is poor; users may be unable to recall any details of the experience
rarely seen on the street today
Amanita muscaria: fly agaric mushroom
  * contains several different hallucinogenic chemicals, including muscarine
    * muscarine: cholinergic agonist
  * muscimole: hallucinogen similar to LSD-like drugs
    * only hallucinogen known to pass unchanged through the system into the urine

Dissociative Anesthetic Hallucinogens

History

Phencyclidine (PCP, angel dust), ketamine, and methoxetamine
PCP
  * first synthesized in 1956
  * tested as an anesthetic, produced tranquilizing effects
  * produced general anesthesia for animals, did not feel pain
  * with humans: experienced hyperexcitability, delirium, and visual disturbances
  * more than 20% of US high school students tried PCP
  * no longer used extensively in veterinary medicine
Ketamine
  * “special K”
  * seen in crystalline powder or in solution
  * can be snorted, injected, taken orally, or smoked
  * one of the most popular club drugs used for 18 to 32 year olds
Pharmacokinetics
  * mechanism: antagonism of NMDA receptors for glutamate (excitatory amino acid)
  * absorbed rapidly after smoking or injection
    * peak [blood] noted 5 to 15 mins after smoking
  * oral administration
    * peak [blood] noted after 2 hours
  * remains in the system unmetabolized for more than 2 days
  * PCP is detectable in urine for several weeks after a single use
Effects of PCP and Ketamine
  * moderate dose (1 to 10 mg) produces feelings of euphoria and numbness resembling OH intoxication
  * slurred speech
  * motor discoordination
  * users are catatonic (ability to move in a normal way is affected) and rigid
  * blank stare, may be aggressive and hyperactive
  * profuse sweating
  * increased HR, BP,
  * Nystagmus: rapid jerky eye movements
  * blurred vision or double vision
  * rarely reported hallucinations
  * dreamlike visions
  * changes in perception of body image, elastigirl
  * distortions of tactile senses
  * effects last 4 to 6 hours, but are variable; may persist for days or weeks at high doses
  * overdoses (more than 20 mg): result in seizures, prolonged coma, death from respiratory failure
  * bad trips: toxic psychosis characterized by paranoia and violence
    * may persist for several days
    * dissociative anesthetics are more likely than other hallucinogens to produce medical or psychiatric complications
  * Ketamine intoxications can create symptoms similar to schizophrenia
  * Ketamine can reduce symptoms of depressions
    * single dose of ketamine can improve symptoms within a few hours

Salvinorin A (Salvia)

plant in the sage family
Salvinorin A is the active chemical in Salvia
southern Mexico, used in religious ceremonies
ingested by chewing leaves or drinking tea
Now, leaves are dried and smoked; concentrated extracts are available for oral use or smoking
Not a scheduled drug at the Federal level
* regulated at the state level
* sold in some states, banned in others
generally smoked b/c appears to be inactive when taken orally
short term hallucinogenic effects
* less than 30 mins in duration; intense trance like state
* effects: visual hallucinations, sensory disturbances, impaired motor control
effective doses (100 to 500 micrograms)
  * {{most potent naturally occurring hallucinogen{{
  * agonist of a subset of kappa opioid receptors
    * not the same receptors that produce pleasurable effects of opiate drugs
    * involved in regulating pain