Chapter 12 - Hallucinogens
Overview
psychotomimetics, psychedelics, & hallucinogens
abbreviated P/P/Hs
long history in aboriginal groups’ rituals
purpose: healing & sacraments
examples
Native American Church: peyote (mescaline) sessions
South American Amazon Indians: yage ceremonies
Mexican Indian tribes: eat mushrooms (psilocybin)
Central-West Africa tribes: iboga (ibogaine) rites
practices continue today by many native groups
seen as decrease users’ psychopathological characteristics
in past 50+ years
therapists began using P/P/Hs as adjunctive therapies
researchers: use P/P/Hs to explore biochemical basis of psychoses
today: most use is recreational
psychotomimetics, psychedelics, & hallucinogens
leads to hallucinations, depersonalization, perceptual disturbances, & thought disturbances
few changes to other bodily functions
effects are dose-dependent
low: alter mood & thoughts, minimal sensory effects
moderate: perceptual distortions, no true hallucinations
high: true hallucinations
terms used to refer to P/P/Hs are confusing
all can lead to hallucinations: called hallucinogens
only rarely lead to psychoses naturally found in humans
usually aren’t taken at high enough doses to mimic natural psychoses
most can alter consciousness & perception
reinforcing, but not due to primary reward center effects
evidence:
users don’t usually comment on mood
talk about perceptual & cognitive aspects of experience
euphoria is cited, but is context specific
some may experience dysphoric reactions
animals won’t self-administer in pure form
will self-administer psychostimulants, sedative-hypnotics, & narcotics
some reports of animals eating plants containing hallucinogenic substances
research on most is very limited
lots of government restraints & little funding
most Schedule I drugs: need special license
most research with animals: how do they communicate their perceptual experience?
common paradigm: learn to discriminate between placebo & a drug
learning phase
inject with saline: reward for pressing left
inject with LSD: reward for pressing right
rats learn discriminations quickly
next, inject with a test compound
if drug → LSD effects press right
if drug doesn’t → LSD effects, press left
can use also to evaluate which transmitter symptoms are being used
4 major classes
serotonergic hallucinogens
effects mediated by alterations in CNS serotonin
LSD
methylated amphetamines
effects mediated by alterations in CNS dopamine & norepinephrine
examples: mescaline, DOM, MDA, MDMA, MDE
anticholinergics
block brain acetylcholine activity
examples: atropa, belladonna, mandrake, henbane, atropine, scopolamine, I-hyoscyamine
dissociative anesthetics
analgesic-anesthetics
examples: PCP, ketamine
Serotonergic Hallucinogens
earliest use: plant species
Aztecs: religious ritual
peyote cactus
psilocybe mushrooms
morning glory seeds
Western Amazon peoples
banisteriopsis (harmine & harmaline)
virola (DMT)
more recently: LSD
1938 - invented in Switzerland
1950s - tried in psychotherapy
early 1960s - celebrities endorsed, usage increased
later 1960s - negative publicity
1970s & 1980s - usage declined, increased again in 90s, and declined deeply since then
Serotonin (5-HT)
12+ receptor subtypes
classified in terms of families (designated by number)
5-HT1, 5-HT2
subtypes within families (designated by letter)
5-HT1A, 5-HT 1B
involvement
5-HT1A: regulation of mood & antidepressant response
5-HT1B: involved in mood, aggression, & anxiety
5-HT2: involved in sexual function; stimulation may → dysfunction
5-HT2A: involved in psychosis
5-HT3: gastrointestinal function & anxiety
most are metabotropic
exception: 5-HT3
termination of action:
taken up by the serotonin transporter system
broken down by monoamine oxidase
effects
PNS
regulates blood vessel contraction
CNS
emotion
anxiety
agitation
GI function
sexual activity
mood
pain sensitivity
aggression
sleep
mental disorders
learning
Serotonergic Hallucinogens: Mechanisms of Action
alter serotonin activity
bind to 5-HT2A receptors
antagonize serotonin
produce hallucinations by disrupting serotonin activity in
thalamus
striatum
cortex
Serotonergic Hallucinogens: Pharmacokinetics
most serotonergic hallucinogens: taken orally
LSD - most potent
lysergic acid amine (morning glory seeds): 5-10% as potent
psilocybin is 1% as potent
mescaline is 1/3000 as potent
Virola (DMT) is snorted or smoked
tolerance develops to most serotonergic hallucinogens
several show cross-tolerance
similar duration of action
most: 8-14 hours
DMT: 1 hour
LSD:
20-60 minutes to produce effects
well-absorbed after oral ingestion
distributed rapidly
metabolism and elimination are also rapid
detected in urine for only 72 hours
Serotonergic Hallucinogens - psychotherapeutic use (3 phases)
1942-1950: could LSD reveal biochemical basis of psychosis?
effects didn’t mimic symptoms of any natural psychosis
1953: useful adjunct for psychotherapeutic techniques?
perhaps LSD could aid in regression therapy
perhaps helpful for OCD, alcoholism, drug addiction, & terminally ill
patients reported decreased desire for addictive pain medications
½ of alcoholics reported 6 months of alcohol abstinence
1960s: LSD began to be seen as an abusable drug
psychiatrists couldn’t describe how LSD should be used or how to document efficacy
non-medical uses → belief it was a public health problem
banned along with peyote & mescaline
psychedelic drug therapy continues unofficially: given IND status
structural & physical properties can be determined
can be tested in lab animals for pharmacological & toxic effects
How do LSD & schizophrenia psychoses differ?
LSD
hallucinations are mostly visual
extreme distortions of existing environment
viewed as neutral or pleasant
responsive to suggestions from others
concerned about interpersonal relations
Schizophrenia
hallucinations are mostly auditory
generally superimposed on environment
viewed as threatening & unpleasant
resistant to suggestion
not concerned about interpersonal relations
schizophrenics who’ve taken LSD can distinguish between the 2 kinds of psychotic states
suggests different mechanisms involved
Serotonergic Hallucinogens: Psychotherapeutic Use
LSD does not produce a model of psychosis
but antipsychotic drugs antagonize LSD effects
no evidence LSD is more useful in psychotherapy than a placebo
Serotonergic Hallucinogens: Effects
risk of fetal damage if taken by pregnant women
no convincing evidence it → chromosome damage in offspring with normal doses
other effects may depend on context & expectations
deep religious feelings, sexual feelings, dreaminess
extreme sadness, anxiety, paranoia
introversion
delusional thoughts
self-destructive behavior: suicide, jumping off roofs
often decreases alertness, cognition
may be due to lack of motivation
does → dose-dependent alterations in perception
colorful visual illusions
complex scenic hallucinations
synesthesia
alterations in perception of time, space, & self
usually visual, auditory, or tactile
may precipitate psychosis/emotional disturbance in vulnerable people
Serotonergic Hallucinogens: Residual Toxicity?
flashbacks
re-experiencing some aspect o the hallucinogenic experience
does LSD leave traces of residual toxicity?
studies: few long-term effects (but methodological issues)
other hallucinogens do not leave traces of residual toxicity
some users experience flashbacks
brief episodes similar to LSD-state
occur weeks of or months after use
usually altered visual perceptions
geometric pseudohallucinations
illusionary movements in periphery
images that trail moving objects
flashes of color
prolonged afterimages
triggered by entering dark room
if bothersome & long-lasting: posthallucinogen perceptual disorder
Methylated Amphetamines
include:
MDMA
DOM
MDA
MDE
all influence serotonin, dopamine, norepinephrine
effects
DOM: prominent visual hallucinations
others: effects similar to amphetamine
few visual hallucinations
Methylated Amphetamines - History & Epidemiology
1900s - developed
1914 - MDMA patented by Merck
1960s
street use of DOM
long duration of action
hallucinogenic effects → bad trips
street use of MDA
received better
fewer perceptual effects than LSD
1970s
MDA use declined with that of LSD
DMA use increased
1980s - MDA & MDMA used in psychotherapy
1985 - MDMA placed on Schedule I
MDMA popular in raves
Methylated Amphetamines - Effects
DOM - similar to LSD or mescaline
MDMA, MDA, MDE: similar
usually taken orally, can be injected or snorted
absorbed rapidly, lasts 6-8 hours
affects serotonin & dopamine
increases release and blocks reuptake
pattern
initial increase in serotonin and dopamine activity
followed by decrease
sympathomimetic effects
muscle tension & teeth grinding
insomnia
claimed effects:
euphoria, emotional warmth, and empathy
lowered defensiveness
increased verbal behavior
MDMA: Withdrawal & Toxicity
withdrawal
not dramatic
drowsiness & muscle pain
depression, paranoia, anxiety
dissipate in a few days
toxicity
increasing emergency room admissions for MDMA
dehydration, heat exhaustion
muscle breakdown, kidney failure
strokes, seizures, heart attacks
usually after high or multiple doses; sometimes after low doses
MDMA: residual effects
animal studies
serotonin toxicity
dose is higher than typical human uses
some human use is high enough
human studies
polydrug problem
heavy MDMA users: decrease serotonin activity
more sleep problems
depressed mood
memory deficits
MDMA users perform worse than non-drug-using controls
don’t perform worse than marijuana-only group
MDMA & PTSD?
people with ptsd can feel relief from MDMA
PTSD - low oxytocin levels (genetics & trauma can decrease it as well)
Anticholinergic Hallucinogens
among oldest hallucinogens
competitive agonists of muscarine acetylcholine (ACH) receptors
only weakly block nicotine receptors
often called belladonna alkaloids
women - used to dilate pupils
e.g., atropa belladonna
middle ages - potions contained anticholinergic mushrooms & herbs
4 deadly nightshades
atropa belladonna: death’s herb
datura stamonium: jamestown week
hyoscyamus niger: herbane
mandragora offinarum: mandrake
today: no law preventing cultivation
risk for recreational use & abuse is very low
have many side effects → not very rewarding, not really a rush feeling
other drugs are available that produce same euphoria without side effects
ACH blockers: atropine, scopolamine
atropine is antidote for nerve gas
Anticholinergic Hallucinogens: Effects
physical effects
dry mouth, blurred vision
loss of motor control
increased heart rate and body temp
respiratory depression may be fatal
psychological effects
dreamlike trance or stupor
delirium and confusion
may describe visions
memory of drug experience is poor
Dissociative Anesthetics
most profound effects: anesthesia
patients are awake, but appear disconnected from environment
PCP: discovered serendipitously
1950s - chemists looked for a new psychoactive drug with therapeutic properties
immediate recognition that it had unique effects on animals
rats - amphetamine-like action, but disrupted coordination
dogs - convulsions
monkeys - calming at low dose & no sensitivity to touch/pain at high dose
PCP’s anesthetic action was most promising for therapeutic uses
most general anesthetics - lethal dose is 2x anesthetic dose
PCP - lethal dose is 10x anesthetic dose (doesn’t decrease vital functions)
tests in humans revealed psychotomimetic properties
PCP → body image distortion, depersonalization, sense of timelessness
in 1/3: PCP → symptoms similar to schizophrenia (days/week)
Dissociative Anesthetics - Pharmacokinetics
antagonize nMDA (glutamate) receptors
may be smoked, snorted, injected, or taken orally
smoked → absorbs rapidly, plasma peaks in 5-15 minutes
orally → slower absorption, peaks at 2 hours
drug remains unmetabolized for 2+ days
metabolites detectable for weeks in urine after single use
Dissociative Anesthetics - Effects
euphoria, numbness
slurred speech, reduced coordination
catatonic & rigid or aggressive and hyperactive
sweating, high heart rate & blood pressure
blurred or double vision
visual hallucinations are rare
changed body perception, distorted sense of touch
distorts sensory impulses to cortex
particularly those for proprioception (where your body is in space)
dreamlike visions
Dissociative Anesthetics - Effects of PCP in Humans
low doses (1-5 mg)
drunken state, floaty euphoria, extremity numbness
colorful visions including moving, glowing, and geometrical patterns
may experience complete absence of time
moderate doses (5 -15 mg)
analgesia, anesthesia, and excited, confused intoxication
decreased communication
body position can be rigidly maintained (cataplexy)
large doses (>15 mg)
psychosis
rare - convulsions, death
has moderately high therapeutic index
tolerance develops to many effects (behavioral adaptations)
can → mild physical dependence
abrupt withdrawal after chronic use → fearfulness, tremors, facial twitches
users also experience cravings following abstinence
Dissociative Anesthetics - Overdose Effects
ketamine
seizures & prolonged coma
respiratory failure and death
lasting cognitive impairment
PCP
paranoia & violence
lasting psychosis & depression
Dissociative Anesthetics - PCP-Induced Psychosis
can → psychotic reactions
normal individuals experience a schizophrenic-like syndrome lasting several hours
those with no previous history whose PCP-induced psychosis lasts ~2 weeks
individuals with history of schizophrenia whose PCP use triggered schizophrenia episode (several weeks)