Transcript Psychopharmacology - Where can my students do assignments that

• Hallucinogenic Drugs
• Drugs that create unusual perceptual and
cognitive distortions
• Many different names
– Psychotomimetic (psychosis mimicking)
• not used these days
– Drugs no longer considered a model for psychosis
– Psychedelic (mind opening)
• Sometimes the term used by those that use the drug class
– Hallucinogenic (hallucination producing)
• Modern pharmacological literature uses this term
• Mescaline
– Obtained from the peyote
cactus plant
– Dried crown of the plant is
know as a mescal button,
or peyote button.
– Buttons can be chewed
raw or cooked and then
eaten
– It is also possible to extract
the mescaline from the
plant and create a relatively
pure powder
• Archeological evidence suggests that natives of
Southwestern United States and Northern Mexico Have
used for thousands of years
• Native Americans used peyote for religious and healing
rituals
• Aldous Huxley (Brave New World)
– Used mescaline and advocated use of hallucinogens
– Some consider his writings about the experiences of
hallucinogens to have spawned the rise of their popularity in the
1960s
• “The Doors of Perception”
• “Heaven and Hell”
• Mescaline is not as readily available in present times as
other hallucinogens
Psilocybin, DMT, and 5-MeO-DMT
• “Shrooms” or “Magic
Mushrooms”
– Numerous species of
mushrooms have
hallucinogenic properties
– Psilocybe mushrooms 
• Depending on the species,
users take about 1-5 g of dried
mushrooms to obtain desired
effects
• Can be consumed raw, boiled
in water to make tea, or
cooked with other foods
– Tends to be bitter alone
• The major ingredient of
mushrooms are psilocybin and
the related compound psilocin
– Psilocin is the actual
psychoactive agent
• Psilocybin is converted by
enzymatic action to psilocin
after ingestion
• Use of hallucinogenic
mushrooms probably goes as
far back as peyote use
– Algerian painting dated to at
least 3500 B.C.
• Shaman?
• Notice mushrooms sprouting
from entire body and held in
hands
• The Spaniards tried to suppress the use of mushrooms when they
conquered the Aztecs in the early 1500s
– They were not completely successful
• The existence of hallucinogenic mushrooms was largely ignored
until the 1950s and 60s
• Timothy Leary lecturer at Harvard ate magic mushrooms while
visiting Mexico in 1959
– Formed the Harvard Psychedelic Drug Research Program
– Purpose was “to teach individuals how to self-administer psychoactive
drugs in order to free their psyches without reliance upon doctors or
institutions”
– Gave psilocybin to students and faculty
– Also experimented with LSD
– Dismissed from Harvard in 1963
– Became leader in psychedelic movement
DMT and 5-MeO-DMT
• DMT and 5-MeO-DMT are
substances found in several
plants indigenous to South
America
• Native tribes make
hallucinogenic snuffs from
these plants
• DMT in this country is usually
sold in powdered form and
taken by smoking
• Synthetic analogs have been
gaining popularity
– Α-methyltryptramine (AMT)
– 5-methoxydiisopropyltryptamine
• Foxy Methoxy or Foxy
LSD
• LSD is a synthetic compound
• Its structure is based on a family of fungal
alkaloids
– Alkaloids are chemical compounds containing
nitrogen that have psychopharmacological
effects
• often found in plants and fungi
LSD first synthesized in 1938
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Albert Hofmann
Worked for a pharmaceutical
company in Switzerland (Sandoz)
Studying ergot
– a substance produced by a
parasitic fungus that can infest rye
and wheat
•
Ergot is extremely toxic to humans
– A core structure of the alkaloids
contained in ergot is lysergic acid
•
Hofmann combined lysergic acid
with other compounds in an
attempt to generate drugs to
stimulate the circulatory system
LSD-25 (LSD)
• The 25th compound synthesized was d-lysergic
acid diethylamide
– LSD-25
• Hoffman accidentally ingested some and had
strange sensations
• Later he took a small amount on purpose
– Had powerful effects
• Sandoz marketed the drug in 1947
– Delysid
• To help neurotic patients uncover repressed thoughts and
feelings
• In the 50s and 60s there were a lot of studies published
on the effects of LSD
– The fact that LSD altered serotonergic activity led many
researchers to consider this a powerful tool to understand
human mental activity and behavior
– Some considered the drug psychotomimetic
• Perhaps could be a model for a schizophrenia
– Replaced now by PCP and Ketamine
– Some considered LSD to be an aid to psychotherapy
• Psycholytic therapy (Europe)
– Psychic loosening or opening
– Release repressed memories and enhance communication with the
therapist
• Psychedelic therapy (US, Canada, Britain)
– Give LSD to patient to help them gain insight through a drug-induced
spiritual experience
• US government explored the possibilities of LSD
as a psychological weapon
• MK-ULTRA (CIA program)
– Designed to investigate LSD as a mind control agent
– At one point they gave LSD to unsuspecting members
of the public to observe behavioral reactions.
• http://soundmedicine.iu.edu/segment.php4?seg=1644
– Check out the above link for a segment from NPRs Sound
Medicine that discusses MK-ULTRA
• As you know LSD was extremely popular in the
hippie culture of the 1960s
• There was a backlash against its use
– Federal laws in 1965 restricted new research on LSD
– Sandoz stopped distributing LSD for research
purposes
– Recreational use of LSD was banned in 1967
– There has been a resurgence in the interest in LSD
research recently
• LSD is usually taken
orally
• A single dose of LSD in
crystalline form is barely
visible to the naked eye
– Larger amounts of LSD are
dissolved in water and then
droplets are applied to a
sheet of paper and dried (a
“blotter”)
– Individual squares of the
blotter are sold as a single
dose “tabs”
Potency and time course of action of Hallucinogenic Drugs
• The potency of hallucinogenic
drugs vary
• Most are taken orally, but as
mentioned earlier DMT is
usually smoked
• For the drugs taken orally
onset of effects usually takes
30-90 minutes
– The trip can take 6-12 hours
– Psilocybin maybe less
• The effects of smoked DMT
are felt within seconds. Peak
effects occur within 5-20
minutes
– Effects are over in an hour or
less
• “businessman’s trip
Psychological and physiological response to hallucinogenics
• Similar across different forms
• Text focuses on LSD
• Four phases of the “trip”
– Onset - 30 minutes to an hour after ingestion
• Visual effects
– Intensification of colors
– Appearance of geometric patterns and strange objects can be
seen with eyes closed
– Plateau phase – next 2 hours or so
• Sense of time begins to slow
• Visual effects become more intense
• Peak phase – about 3 hours into trip; lasts
another 2 or 3 hours
– May feel like in another world in which time has been
suspended
– Continuous stream of bizarre distorted images
• Can be beautiful, or menacing
– May experience synesthesia
• Crossing over of senses – colors heard
• Come down phase – 2 more hours or so
– Most effects are gone by the end
– User may not feel completely normal until the next
day
• hallucinogens can produce other psychological
effects in addition to the phases of sensoryperceptual effects above
– Emotional shifts
• Euphoria
• Anxiety
• Fear
– Feelings of depersonalization
• Being outside oneself
– Disruption of logical thought
• Sometimes the LSD experience is viewed as mystical or
spiritually enlightening
– Good trip
• Sometimes it can be disturbing and frightening
– Bad trip
• Good trip or bad trip may depend in part on
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The dose
Individuals personality
Expectations
Previous experience
Social setting
• Can’t really predict the outcome of an LSD trip in
advance
Physiological response to hallucinogens
• LSD effects reflect activation of the sympathetic
response
– Pupil dilation
– Increased
• Heart rate
• Blood pressure
• Body temperature
• Can cause
– Dizziness
– Nausea
– Vomiting
• These effects are more likely with peyote and psilocybin
Indoleamine hallucinogens
• Most hallucinogens
have either a
serotonin-like or a
catecholamine-like
structure
– Serotonin-like or
indolamine
hallucinogens
• LSD, Psilocybin,
psilocyn, DMT, 5-MeODMT, synthetic
tryptamines
Phenethylamine hallucinogens
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Catecholamine-like hallucinogens
– Notice their similarity to
Norepinephrine
– of course they are also structurally
similar to DA
• Remember Amphetamine chapter
•
Mescaline is the catecholaminelike hallucinogen that we have
discussed
– but there are also forms of
amphetamines that have
hallucinogenic properties
• DOM
• TMA
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Together these drugs are known
as phenethylamine hallucinogens
Hallucinogens are 5-HT2 receptor agonists
• How hallucinogens cause dramatic
cognitive and perceptual effects is not well
understood
• Evidence for serotonergic effects
• LSD binds with high affinity to multiple
serotonergic receptor subtypes
– 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT6,
5-HT7
• If we compare the
indolamine and
phenethylamine
hallucinogen families we
find that both bind to only
a couple of serotonin
receptor subtypes
– 5-HT2A and 5-HT2C
• This suggests those
receptor subtypes may
play a key role
• There is not a lot of human experimental work on the
hallucinogens
• Here is 1 nice study
– Vollenweider et al. (1998) studied psilocybin.
• Found that visual illusions and hallucinations produced
by these drugs were blocked by antagonists of the 5HT2A receptor.
– Ketanserin
– Risperidone
• Also blocks D2 receptors
• Note in next graph that haloperidol (another D2 antagonist) did not
block these effects
– Ruling out D2 effects
14.7 Blockade of psilocybin-induced visual illusions and hallucinations
• Since there is not a lot of
human work, animal
studies are very
important.
• Drug discrimination
studies are quite useful
here
– Train to discriminate LSD
from saline injection
• LSD lever
• Saline lever
• Then the animals were tested
with various doses of particular
5-HT2A receptor antagonists
• Notice all 3 antagonists
decreased responding to The
LSD lever.
– Switched to saline lever
– Implies these antagonists
blocked the subjective effects
of LSD
• Drugs that have higher affinity
for 5-HT2A do a better job of
blocking these effects
Tolerance
• Most hallucinogenic drugs cause rapid tolerance
with repeated use
• Humans taking LSD for 4 days showed nearly
complete tolerance by day 4
– Likely the result of down regulation of 5-HT2A
receptors
– A 2005 study with mice showed down regulation of 5HT2A receptors after repeated LSD exposure
• Takes 3 or 4 days for tolerance to go away
Neural Mechanisms of hallucinations
• One theory is that the locus coeruleus
plays an important role
– Remember- dense cluster of NE neurons in
the pons
– Receives information from all the major
sensory systems and sends that information
to all areas of the cortex.
Neural Mechanisms of hallucinations
• Aghajanian et al found that LSD and mescaline
decreased spontaneous firing of neurons in the
rat LC
• However, they also found that the LC cells were
more easily excited by sensory information
• Put together, these effects make the LC far more
sensitive to sensory input.
– Baseline is lowered
– Responsivity increased
Neural Mechanisms of hallucinations
• Perhaps the increased sensitivity of the LC
is the mechanism of perceptual distortion
and hallucination following ingestion of
LSD
– Studies using fMRI with shizophrenic patients
experiencing hallucinations show increased
activity in cortical regions that normally code
that sense
• Visual – occipital
• Auditory – temporal
• Other researchers posit that areas such as the
prefrontal cortex, striatum, and thalamus (fronto
sub-cortical circuits) might serve as a gating
mechanism for sensory information.
– The idea is that the hallucinogens may open the gate,
thus, flooding the cortex with information
– These researchers believe that this might also explain
the cognitive disturbances common with
hallucinogenic drugs as well
Addiction?
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Hallucinogens are not considered addictive
People usually do not binge
Do not cause cravings
Do not cause physical dependence or withdrawal
Do not support self-administration in animals
Doesn’t seem possible to overdose
– No documented human deaths
– Eight individuals have been documented as taking massive doses
• Snorted crystaline form (mistaken for cocaine)
– Remember a barely visual grain is psychoactive
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Comatose state
Vomiting
Hyperthermia
Light gastric bleeding
Respiratory problems
They all survived without residual effects
• Despite lack of addictive potential and lack of
overdose issues, the use of LSD can have
consequences
– Bad trips
– Flashbacks
• Hallucinogen persisting perception disorder (HPPD)
– Long lasting flashbacks causing major impairment or
disturbance
– Few documented cases
– Psychotic breakdown?
• Prolonged psychotic episodes following LSD use invariably
involve individuals
– Already diagnosed with a psychiatric disorder
– That exhibited prepsychotic symptoms prior to taking the drug
PCP and Ketamine
• PCP and ketamine were both initially developed as
anesthetics.
– PCP
• 1-(1-phenylcyclohexyl) piperdine
– AKA phencylclidine
• Developed in the 1950s as an anesthetic
• Produced unusual anesthesia
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No responsiveness to nociceptive stimuli
But, not typical relaxed unconsciousness (like seen with barbiturates).
Trance-like or catatonic-like state
Vacant expression
Fixed staring eyes
Maintenance of muscle tone
» Not uncommon to have rigidity or waxy flexibility like seen in
catatonic schizophrenics
• PCP was initially considered a promosing
anesthetic
– Did not produce respiratory depression like seen with
barbiturates
• High therapeutic index
• But some patients had problematic reactions
– Agitation – rather than quieting
– Postoperative effects ranging from blurred vision,
dizziness, and mild disorientation…to hallucinations,
severe agitation, and violence.
• Clinical use of PCP was terminated in 1965
• PCP became a more popular illicit drug in
1967.
– AKA – “Angel dust”; “hog”
– Never was as popular as marijuana or even
cocaine or heroin
• Ketamine was developed as a safer alternative
to PCP
• First synthesized in 1962
– CI-581 ---- later renamed ketamine
• Less potent and shorter acting than PCP
• Valuable anesthetic particularly for children
– Also animals
• Currently available with prescription
– Ketaset
– Ketalar
– Vetalar
Route of administration
• PCP is generally obtained
in powder form
• Can be ingested by any
common route
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Orally
Intranasally
IV
IM
Smoked
• Applied as a liquid to a
cigarette
Route of administration
• Ketamine is marketed
as an injectable liquid
• Street sellers
commonly evaporate
the liquid to yield a
powder.
– Can be snorted
– Compressed into a pill
• AKA: “K,” “special K,”
and “cat valium.”
• Studies form the 50s and 60s found that subanesthetic
doses of PCP produce
– Feeling of being detached from body
• Dissociation
– Sensations of vertigo or floating, numbness.
– Dream like state
– Affective changes
• Drowsiness, apathy, negativism
• Sometimes hostility toward experimenters
• Sometimes euphoria
– Cognitive disorganization
• Difficulty maintaining concentration
• Deficiency in abstract thinking
• Halting speech
Subjective effects of ketamine
• Low doses of ketamine produce reactions
similar to what occurs with PCP
• High doses can produce dissociative anesthesia
– Lose mental contact with environment for 10 minutes
or so
– Eyes open
– Maintain muscle tone
• Some have described the dissocative state as a
“near-death” experience
– Sometimes called “K-hole”
• Sometimes spiritually uplifting
• Sometimes terrifying
Reinforcement
• PCP and ketamine support self-administration in several
species
• Rhesus monkeys self-administered PCP at levels to
maintain continuous intoxication
– Could not stand up.
– Lying or sitting on floor near lever
• PCP and ketamine activate midbrain DA cell firing.
– Stimulate DA release particularly in prefrontal cortex
• Rats will self-administer PCP directly in the NA
– This affect may be driven by inhibition of glutamatergic input to
the NA rather affecting the DA system
PCP and Ketamine’s action at the NA
• Cocaine and amphetamine are indirect DA
agonists
– DA normally inhibits NA
– Slowing NA activity = reinforcement
• PCP and ketamine are antagonists of
Glutamate (at NMDA receptor)
– Glutamate normally excites NA
– Slowing NA activity = reinforcement
14.12 Self-administration of PCP into the nucleus accumbens shell by rats (Part 1)
PCP and ketamine are noncompetitive antagonists of the NMDA receptor
• NMDA is an ionotropic receptor that responds to
glutamate
• NMDA and ketamine block at the receptor by
binding to a site different from where glutamate
binds
– Making them noncompetitive antagonists
– Remember the binding site is inside the channel
• NMDA receptors found throughout the brain
including the cerebral cortex and hippocampus
– This probably leads to the cognitive deficits
• The use of ketamine seems to be
increasing
• Studies of ketamine use indicate that it
can cause strong addiction
• People also take increasing doses
indicating tolerance
Model of schizophrenia
• Acute PCP or ketamine exposure causes
perceptual, cognitive, and affective responses
closely resembling symptoms of schizophrenia
– Can cause positive and negative symptoms
• Positive
– Hallucinations
– Bizarre thought content
• Negative
– Blunted affect
– Emotional withdrawal
– Slowed motor response
– Some of the symptoms can persist for days
• Perceptual distortion
• Magical ideation
• Animal models
– Evidence that chronic PCP administration can
cause lasting deficits that mimic some
symptoms of schizophrenia
– Show deficits on tasks that require prefrontal
cortex function
14.13 Ketamine administration produces a dose-dependent increase in psychotic-like symptoms