Transcript Hallucinogens - People Server at UNCW

Psychedelic/Hallucinogens- Chpt 12
• Primary effect is to produce perceptual
changes & hallucinations
• Can influence several sensory systems,
perception of time, space & events
Structure of hallucinogens
• Most Hallucinogenic drugs have either a serotonin-like or a
catecholamine-like structure
• Serotonin-like are also known as indoleamine
– LSD, psilocybin, psilocin, DMT and 5-MeO-DMT
• Catecholamine-like aka phenenthylamine
– mescaline
– has structural similarities to NE & amphetamine
Mescalin
e
5-HT
DMT
Different Types of Psychedelics-based
on their neurochemical characteristics
•
Serotonergic
– LSD
– Psilocybin/Psilocin
– DMT - Ayahuasca
– Bufotenine
•
Ololiuqui (oh-low-lee-oo-kee)
• Catecholamine-like
– Mescaline
– MDMA (ecstasy)
• MDA
• MDE
– DOM
– Myristin and Elemicin
• Cholinergic
– Muscarine
– Scopolamine
• Glutamatergic
– PCP
– Ketamine
– Dextromethorphan
• Opioid
– Salvinorin A
Pharmacology of Hallucinogenic
Drugs
• Pyschedelic effects
begin within 30-90
min (oral)

• LSD or mescaline trip lasts
for 6-12 hrs; Psilocybin
dissipates sooner
• DMT effects user within
seconds and dissipates in
an hour or less
Drug
Route of
Admin
Typical Dose
Range
LSD
Oral
.05-.10 mg
Psilocybin
Oral
10-20 mg
Mescaline
Oral
200-500 mg
DMT
Smoking
20-50 mg
 Depicts the typical dose range
taken by recreational users
(psilocybin is most potent and
mescaline is the least)
Physiological Responses
• Activation of the sympathetic nervous system
• Pupil dilation, small increases in heart rate,
body temp and blood pressure
• Dizziness, nausea, and vomiting
Psychological Effects
•
State of intoxication usually called a “trip”
• Trip can be divided into four stages:
1. Onset – 30 min to 1 hour
visual effects begin
2. Plateau – next 2 hours
sense of time slows, visual effects
intensify
3. Peak – after about 3 hrs and lasts
2-3 hours
“in another world”, synesthesia
4. Come down – 2 hours
May take up until next day to feel
normal again
•
Other psychological effects include depersonalization, anxious or fearful state, disruption of logical
thought.
•
“Good trip” versus “Bad trip”: depends on dose, user’s personality, expectations, previous
experiences, physical and social settings
Neural mechanism
• Experimental animal studies
– Lack of relevant human studies
• Location of critical receptors
– Locus coeruleus (LC) – NE neurons
• Receives/integrates input from all major sensory systems
• Sends information to cortex (sensory cortex)
• Activation of receptors
– How does it produce sensory/cognitive distortions?
Experimental receptor study
• Vollenweider (1998)
– Administration of antagonists
• Risperidone, Ketanserin (5-HT2A + D2 DA)
– Decreased drug-induced visual illusions/hallucinations
• Haloperidol (Only D2 DA – Not 5-HT2A)
– Completely failed to prevent hallucinogenic effects
• 5-HT2A is key mediator of hallucinogenic action
– Tolerance acquired via down-regulation of
receptors
– Very rapid tolerance – nearly complete in 4 days
Receptor Activation
• Serotonergic system involved in process
– Perceptual and cognitive effects
• High affinity for 5-HT receptor subtypes (LSD)
– 5-HT1A,B,D, 5-HT2A,C, 5-HT5A, 5-HT6, 5-HT7
• LSD compared to phenylethylamine drugs
– Only receptors in common
• 5-HT2A, 5-HT2C
Two mechanism theories
Administration of hallucinogenic drugs
Aghajanian et al. (1999)
Decrease spontaneous firing, enhanced excitation
Drug intake  LC more sensitive to sensory input
Generation of hallucinations
Vollenweider et al. (2001)
Disrupt frontal cortex/striatum/thalamus circuitry
Drug intake  interfere with sensory info ‘gating’
Information overload at cortical level
Hallucinogenic drug problems
Serious drug side effects
‘Bad trip’ – anxiety/panic
Interaction between drug, emotional state, environment
Flashbacks
Re-experience perceptual symptom long after use
Neural mechanism presently unknown
Psychotic breakdown
Most severe adverse reaction
Mental state – loss of contact with reality
Typically occurs with psychiatric disorder
Serotonergic
Psychdelics
Serotonergic Hallucinogens
•
•
•
•
•
Lysergic acid diethylamide (LSD, Acid)
Psilocybin-Psilocybe mushrooms-Shrooms
Mescaline-Peyote cactus
Ergine-Morning glory
Harmaline-Ayahuasca,Yage’
LYSERGIC ACID DIETHYLAMIDE (LSD)
• Lysergic acid – Derived from ergot alkaloids
• Ergot is a poisonous fungus that infects rye &
other grains & grasses
• Albert Hoffman: 1938 - synthesized #25 in
series of new molecules doing ergot alkaloid
chemistry
• 1943 - returned to #25 making new
batch & absorbed some through skin
Aldous Huxley
Albert Hofmann-Discovered LSD
Timothy Leary and Ken Kesey
Doses of Acid
Effects of LSD etc...
• Sympathomimetic
• Visual hallucinations
Visual Hallucinations
•
•
•
•
•
Enhanced color perception
Flickering of the visual field
Perception of motion
Synesthesia
Form constants
Form Constants
• Lattice Pattern
Form Constants
• Lattice Pattern
• Tunnel/Vortex
Form Constants
• Lattice Pattern
• Tunnel/Vortex
• Spiral Explosion
Visual Hallucinations
•
•
•
•
•
Enhanced color perception
Flickering of the visual field
Perception of motion
Synesthesia
Form constants
Form Constants
• Lattice Pattern
• Tunnel/Vortex
• Spiral Explosion
Effects of LSD etc...
•
•
•
•
Sympathomimetic
Visual hallucinations
Altered consciousness
Tolerance (but no dependence)
Adverse Effects: Myth & Reality
• Birth defects/chromosome damage
– Myth!
• Acute Psychotic Reactions (Bad Trips)
– Fairly Common
• Use 7 times and legally insane
– Myth!
• Residual Psychosis
– Rare; not certainly related to LSD
Adverse Effects: Myth & Reality
• Flashbacks
– Fairly common among heavy users
• For some people, flashbacks are constant
– Rare, but true: hallucinogen persisting perception
disorder
• Stored in spine?
– Myth—Causes of flashbacks unclear
LSD in the USA
Came to U.S. in 1950s in two ways:
• Clinical usage: Supplied to psychologists
and psychiatrists
– encouraged their taking drug
• Military Usage: U.S. military and CIA as
incapacitating agent and truth drug
• U.S. government gave LSD to
unsuspecting individuals to study effects
LSD in the USA
• 1960s - popular use advocates
– East Coast: Timothy Leary (clinical
psychologist at Harvard)
– West Coast: Ken Kesey (noted author)
• graduate student in California got dose in
psychology study
• shortly after this goes to work in psychiatry
• year later, writes One Flew Over The Cuckoo's
Nest
LSD in the USA
• Spread through country with huge
publicity until peak 1968 to 1972
• Schedule I in 1968
• Stuffy politicians didn’t know what to do
because LSD was used by white, middle
to upper class, college students
• Early 1990s - LSD came back
LSD & Neurotransmission
• Binds to 5-HT2A
receptors
– agonist effect
• Increases amount of
sensory information
getting to cortex through
overriding filter
mechanisms
• This is how the drug
influences perception,
especially for vision
Pharmacology of LSD
Pharmacological Effects
• Effects heavily dependent
on dose taken
– not just intensity of effects,
but type of effects
• Low doses = mild
perceptual alterations
– comparable to effects of
marijuana use, but greater
clarity
Effects of LSD
High Doses
• progression through mental and
emotional experiences
• 6-12 hrs duration
• Each trip unique,
highly
dependent upon setting and
personal expectations
• Can alter subjects’ emotional
feelings during trip by
experimenter’s previous behavior
– warm and supportive or
suspicious and nonsupportive
Effects of LSD
Effects of drug come on in about 30 min
• first signs are autonomic activation
• followed by overt behavioral signs - loosening of
emotional inhibitions
– giddiness, laughter for no reason
– mood euphoric and expansive, but labile mood
swings notable
• abnormal color sensations, luminescence
• colors reported as more brilliant
Effects of LSD
• space and time disorders
• added depth with loss of perspective up/down altered
• close in space influenced more than
distant
• general slowing of time reported
LSD Hallucinations
 gratings, latticework,
honeycomb, chessboard,
 tunnels, funnels, alleys, cones,
vessels, and spirals
 can be present with eyes open or
closed
 involve bright light in center
with figures moving in from
periphery
 forms appear to move in depth
and take on color shades, red
common
 Sounds can take on visual
forms
 music may take on enhanced
meaning or intensity
LSD & Bad Trips
• Psychological impact - traumatizing, imagery
dark, insights appalling
• Usually occur in novice users, feel out of control
• Generally negative set and setting are key
contributing factors
• Can lead to suicide or prolonged psychotic
reaction
• Can usually be talked down from a bad trip
LSD & Flashbacks
Spontaneous recurrence of trip after period of
normalcy
• can occur after long periods of abstinence
• more common after multiple high dose use
• prolonged afterimages for days and weeks after
– tripping mechanism unknown
• can be brought on by other drugs or setting
• most commonly reported in low light situations
• not intrinsically dangerous and usually go away
Psilocybin/Psilocin
• Magic Mushrooms,
Liberty Caps
– Central America and
northwestern U.S.
– Last about 6-10 hours
– Need a lot to get same
effect as LSD
– 5-HT2A agonist
– Same basic effects as LSD
– Mushrooms occasionally
toxic
Psilocybe Mushrooms-psilocybin
Psilocybe Mushrooms-psilocybin
Psilocybin, DMT, & 5-MeO-DMT
 Psilocybin
• “magic mushrooms” or “shrooms”
– Fungi that manufactured alkaloids with hallucinogenic
properties
• Per os
– Eaten raw, boiled in water to make tea, or cooked with
other foods to cover its bitter flavor
• Major ingredients
– Psilocybin and related compound psilcon, the actual
psychoactive agent psilocybin is converted to
Psilocybin, DMT, & 5-MeO-DMT (cont’d)
 DMT (dimethyltryptamine)
 Derived from plants in South America
 Devoid of psychoactivity when taken orally
Except with ayahauasca, “vine of the soul”
 Vines contribute to alkaloids called β-carbolines
Hypothesized to inhibit the enzyme monoamine
oxidase which breaks down DMT
 In solid powder form and smoked
 5-MeO-DMT (5-methoxy-dimethyltryptamine)
 “Foxy Methoxy”
 Oral active synthetic DMT analog
DMT
• Dimethyltriptamine
– 5-HT2A agonist
– Alkaloid
– Often smoked
– Main ingredient in Ayahuasca
– Same effects as LSD
Bufotenine
• Dimethyl-serotonin
– A product of abnormal
serotonin breakdown
– Like LSD and others
– Can occur in urine of
people with psychiatric
disorders
• Psychosis
• Paranoia
• Depression
Ololiuqui
• Substance found in morning glory seeds
• Similar to LSD
• Significant nausea, vomiting and cramping
Tolerance/Dependence
•
•
•
•
Not significant producers of tolerance or dependence
No withdrawal either
People and animals do not self-administer
Problems related to the things people do while
under the influence
–
–
–
–
Accidents
Suicide
Aggression/violence
Toxic reactions
Catecholamine-like
Psychedelics
Mescaline
• Active drug in peyote
• Structurally similar to NE
• However, most of the effect
is mediated by our friend,
the 5-HT2A agonist action
• Legal for members of the
Native American Church
Peyote cactus-mescaline
Religious Use of Hallucinogens
• Right to peyote ritual is protected for Native
Americans
• Supreme Court is reviewing religious use of
hoasca tea (DMT) now (November, 2005)
Peyote cactus-mescaline
Mescaline
• Peyote cactus
– Mescal (peyote) button
– Native to SW United States and N Mexico
• Administration
– Chewed raw or cooked and eaten
– Pure powder form
• High cost of synthesis and lacks a large market
Ecstasy
• MDMA (methylene-dioxy-methamphetamine)
• Synthesized in 1912
• Structurally related to amphetamines
– Sympathomimetic
– Weak in altering perceptual functions
– But strong effects on emotions
- empathogen
O
– Used in combo with psychotherapy CH 3
O
CH 2 CH
Of interest: http://www.biopsychiatry.com/interview/index.html
MDMA
NH
CH 3
Methylated Amphetamines
• Methylenedioxymethamphetamine (MDMA,
Ecstasy, XTC)
• Methylenedioxyamphetamine (MDA)
Ecstasy (MDMA): Psychological Effects
• Increased alertness, arousal, insomnia-stimulant effects
• Euphoria, increased emotional warmth
• Increased empathy and insight?
• Hallucinogenic effects are largely absent
Ecstasy (MDMA): Physiological Effects
• Sympathomimetic
• Bruxism & Trismus—teeth grinding & jaw
clenching (pacifiers)
• Dehydration/Overhydration
• Hyperthermia
• Tachycardia
• Collapse/Overdose death
Percent Using
Percent
School Seniors
Seniors reporting
Percent
HighHigh
School
reporting
use during their Senior year
MDMAMDMA
use
during their Senior year
(Johnston, O'Malley,Bachman
(Johnston,
O'Malley,Bachman
& Schulenberg,
2005)
& Schulenberg, 2005)
8
6
4
2
98
96
96
98
00
Year
02
00
04
06
Ecstasy and the brain
• MDMA increases release and blocks reuptake
of serotonin
• MDMA also increases release of dopamine,
and norepinephrine
• Long term/Permanent depletion of
serotonin—damage to serotonin neurons in
nonhumans
Ecstasy and the brain:
Preclinical research
• Serotonin depletion, damage to serotonergic
neurons reported in several species including rats
and primates (see Morton, 2005 for a review)
• Effects were present in primate brain 7 years after
MDMA exposure Hatzidimitrious et al., 1999)
• Mechanism of these effects?
Ecstasy and the brain:
The Retraction
• Ricaurte et al. (2002) reported in Science that
MDMA produced severe dopamine
neurotoxicity in primates at doses in the range
commonly encountered by human users.
• Ricaurte’s 2003 retraction and the fallout
Are doses used in preclinical research too
high?
• Although neurotoxic doses in non-humans (520 mg/kg twice or more/day for several days)
are generally higher than would be typical of
human use, people often take several tablets
at a time or throughout an night’s binge and a
tablet may contain up to 300 mg: 4-5 mg/kg in
an average person.
Clinical Research: Ecstasy in humans
• Topp et al. (1999) Australia study
• Physical side effects
– Loss of energy (65%)
– Muscular aches (60%)
– Hot/cold flashes (48%)
– Numbness (47%)
– Profuse sweating (43%)
– Tremors (42%)
Ecstasy in humans
• Topp et al. (1999) Australia study:
Psychological side effects
– Irritability (63%)
– Sleep difficulty (56%)
– Depression (56%)
– Confusion (47%)
– Anxiety (45%)
– Paranoia (40%)
Clinical Research: Ecstasy in humans
• McCann et al. (1999)--MDMA users
performance impaired in tasks of attention
and STM--decreased serotonin in CSF
• Semple et al. (1999)--decreased serotonin
transporter activity and cognitive impairment
• Holes in the brain?
Ecstasy in humans
– Morgan (2000) review: Heavy users more
depression, sleep disorders, memory problems
than controls
Ecstasy in humans
– Morgan (2000) Heavy users more depression,
sleep disorders, memory problems than controls
– What is the proper control group?
– Parrott et al. (2001) Heavy ecstasy users more
depression than non-users, but not more than
other drug users.
Ecstasy in humans
– Morgan (2000) Heavy users more depression,
sleep disorders, memory problems than controls
– What is the proper control group?
– Parrot et al. (2001) Heavy ecstasy users more
depression than non-users, but not more than
other drug users.
– Croft et al. (2001) Memory deficits in MDMA
users, but also in group matched for THC use that
used no MDMA
Ecstasy in humans
Thomasius et al. 2003 Psychopharmacology:
Compared 30 current & 31 ex-MDMA users with 29
polydrug users (no MDMA) and 30 non-users
No differences in psychopathology between MDMA
and PD groups (all showed more than NU) on
Symptom Check List
Ecstasy in humans
Thomasius et al. 2003 Psychopharmacology:
Compared 30 current & 31 ex-MDMA users with 29
polydrug users (no MDMA) and 30 non-users
No differences in cognitive battery between MDMA
and PD groups
Ecstasy in humans
Thomasius et al. 2003 Psychopharmacology:
Compared 30 current & 31 ex-MDMA users with 29
polydrug users (no MDMA) and 30 non-users
PET scans showed reduced serotonin transport
availability in some brain regions only in current
MDMA users—suggests recovery after a period of
abstinence (see also DeWin et al, 2004; McCann
et al, 2005)
Why differing outcomes?
• Sampling issues and difficulties in matching
controls
• Different behavioral & neurochemical measures
• Problems with self-report (e.g., many different
drugs are sold as MDMA (dancesafe.org)
Ecstasy and the brain: What do we
know?
• MDMA increases release and blocks reuptake
of serotonin (increased release of DA and NE
as well)
• Long term alterations of serotonin activity in
nonhumans & humans--
Ecstasy and the brain: What do we
need to know?
• What levels of use produce the serotonin effects and
how long-term are they?
• Is there functional significance?
• Human data—Memory? Affect?
• Clinical trial for PTSD
Ecstasy and the brain: What do we
need to know?
• Animal data—Does MDMA produce learning
and memory deficits in rats: the UNCW
project
• Student investigators: Laura Bullard, Miles
Hulick, Brooke Poerstal, Becky RayburnReeves, Andrea Robinson
History
• Patented by Merck in 1914
• Advocated by some as adjunct to
psychotherapy (1970s-80s)
• Picked up the name “ecstasy” & became
significant street drug (1980s)
• Schedule I drug (1986)
• Prototype “club drug” (1990s)
MDMA: Prototype Club Drug
Pharmacodynamics
Monoamine neurotransmission
– increase synaptic DA and 5-HT
– blocks 5-HT transporter
– enters neuron and causes release of 5-HT
Ecstasy Effects
• Stimulant effects typically noted shortly after
ingestion
–
–
–
–
–
–
–
increased heart rate
increased blood pressure
dry mouth
decreased appetite
increased alertness
elevated mood
jaw clenching
Ecstasy Effects
Subjective Effects
euphoria
increased physical and emotional energy
heightened sensual awareness
subjective feeling of increased closeness or enhanced communication
Cognitive Effects
memory loss
X Tox
• Malignant hyperthermia and dehydration
• Idiopathic toxic response (not common but
nasty)
– Renal failure
– Rhabdomyolysis – disintegration of muscle tissue
• Street X is even more of a problem because
it’s not always X or may have other drugs
X Tox
 Potent neurotoxin
•
•
•
•
1-2 times street dose
depletes forebrain 5-HT (not DA)
Kills the transporter receptor (SSRI)
Degeneration of 5-HT terminals
• Fine axons from dorsal raphe
• Can get 30% loss with single injection
• Up to 80% with repeated injections
 Can induce psychiatric disturbance in vulnerable
individuals. Treatment refractory depression
MDMA & MDA neurotoxicity
5-HT immunoreactive fibers in rat parietal cortex
PCA
Normal
MDA
9.9
Squirrel
monkeys 18
mo post-trtmt
Control
5-HT immunoreactivity
MDMA
McCann et al.
(1997)
Neocortex
Hippocampus
Caudate
What is PMA?
• Paramethoxy-amphetamine
• "Death" "Mitsubishi Double Stack"
"Killer" "Red Mitsubishi"
• Substitute for MDMA
• Cheaper to make
• Slower, longer effects
• More hallucinogenic
• Incidence of toxic side effects much higher than
MDMA (narrow safety margin)
Designer Psychedelics
• DOM, MDA, DMA, MDE, TMA, AMT, 5MeODIPT
• All structurally related to mescaline and
methamphetamine; therefore MDMA.
• MDA is a metabolite of MDMA. May be
responsible for much of the MDMA effect.
Myristin and Elemicin
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•
•
•
Found in nutmeg and mace
Structurally similar to mescaline
Significant nausea and vomiting
The sick usually limit use
Glutamatergic
Psychedelics
Dissociative Anesthetics
Anesthetic Hallucinogens
• Phencyclidine (PCP, Angel dust,
Lovely)
• Ketamine (Special K)
Anesthetic Hallucinogens
• Glutamate antagonists
• Euphoria, numbness, loss of motor
coordination, blurred vision
• Nystagmus
• Distortions of body image, not visual
hallucinations
• High rate of psychotic episodes some longterm
Phencyclidine
 PCP
 NMDA receptor antagonist
Blocks the function of glutamate
 Used as an analgesic and anesthetic
 Can be administered by any route
 Oddly enough, animals self-administer
(euphoria)
 Induces amnesia and true psychosis
Hallucinations, paranoia, agitation, dissociation
 Higher doses lead to stupor, coma
seizures, death
 A perfect example of a Schedule I drug
Ketamine
• Special K
• Very similar to PCP, not as
powerful
• Liquid, but can be
powdered for snorting or
smoking
• But just as dumb, stupid,
useless and unsafe
• Another perfect example of
a Schedule I drug
Subjective Effects of PCP/Ketamine
• Sensations of light coming through the body and/or
colorful visions
• Complete loss of time sense
• Bizarre distortions of body shape or size
• Altered perception of body consistency
• Sensations of floating or hovering in space
• Feelings of leaving one’s body
• Visions of spiritual or supernatural beings
• Emotions ranging from euphoria to hositlity
Dalgarno & Shewan (1996)
Dextromethorphan
•
•
•
•
•
Active ingredient in most OTC cough medicine
NMDA receptor blockade at high doses
Mostly teenage males abuse it
Like PCP and K at 20-30 X OTC dose
Coricidin –Bad news
Cholinergic
Hallucinogens
Anticholinergic hallucinogens
• Atropine-from the Deadly nightshade, Datura,
Jimson weed, and Mandrake
• Scopolamine-from Datura, Jimson weed,
Mandrake and Henbane
Datura
Jimson weed
Muscarine/Muscimol
 Found in mushrooms
(Amanita Muscaria)
 Muscimol is a GABAA
agonist
 Trance-like, dreamy state
with dreamlike illusions
 Like Ambien
 Muscarine is an
Acetylcholine agonist
(muscarinic receptors)
 Not psychotropic
 Peripheral effects: sweating,
limb twitching, seizure
activity
Found in – Atropa
belladonna, Datura
Stramonium, Henbane
Acetylcholine receptor
(muscarinic) antagonists
 Dissociatives that
induces delirium ,
hallucinations, and
amnesia
 Classic anti-cholinergic
symptoms
Hot as hell
Dry as a bone
Mad as a hatter
Blind as a bat
Red as a beet
Used in the treatment
of motion sickness & to
dilate pupils during eyeexams.
Atropine & Scopolamine
Anticholinergic effects
• Dry mouth, blurred vision, loss of motor
control
• Dream-like trance state
• Little or no memory of experience
Comes from a plant in the
mint family
Salvia Divinorum
Affinity for kappa opioid
receptors
Agonist action
Like LSD and psilocybin
Fresh leaves are chewed
and left in mouth
Dried leaves smoked
Not effective if taken orally
Most potent, but not most
powerful, of all naturally
occurring hallucinogens
It’s still legal, but not likely
for long
Opioid Hallucinogen - Salvinorin A
Salvia Divinorum
• Plant used by the Mazatec people of Southern
Mexico: Diviner’s sage—leaves chewed or smoked
• Active drug = salvinorum A (affects Kappa receptors)-most potent natural hallucinogen (100 microgram
ED50)
• Brief (30-60 min) intense trip: visual hallucinations,
dissociative state, some bad trips, recent highly
publicized suicide
• Marketed legally in US (in most states) as herbal
dietary supplement—currently under DEA review