Hallucinogenic Drugs

1

• 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

2

• 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

3

• 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

4
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

5

• 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

6

• 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

7
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
• ?-methyltryptramine (AMT)
• 5-methoxy-diisopropyltryptamine
• Foxy Methoxy or Foxy

8
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

9
LSD first synthesized in 1938

• 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

10
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

11

• 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

12

• 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?seg1644
• Check out the above link for a segment from NPRs
  Sound Medicine that discusses MK-ULTRA

13

• 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

14

• 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

15
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
• businessmans trip

16
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

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• 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

18

• hallucinogens can produce other psychological
  effects in addition to the phases of
  sensory-perceptual effects above
• Emotional shifts
• Euphoria
• Anxiety
• Fear
• Feelings of depersonalization
• Being outside oneself
• Disruption of logical thought

19

• 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
• The dose
• Individuals personality
• Expectations
• Previous experience
• Social setting
• Cant really predict the outcome of an LSD trip
  in advance

20
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

21
Indoleamine hallucinogens

• Most hallucinogens have either a serotonin-like
  or a catecholamine-like structure
• Serotonin-like or indolamine hallucinogens
• LSD, Psilocybin, psilocyn, DMT, 5-MeO-DMT,
  synthetic tryptamines

22
Phenethylamine hallucinogens

• Catecholamine-like hallucinogens
• Notice their similarity to Norepinephrine
• of course they are also structurally similar to
  DA
• Remember Amphetamine chapter
• Mescaline is the catecholamine-like hallucinogen
  that we have discussed
• but there are also forms of amphetamines that
  have hallucinogenic properties
• DOM
• TMA
• Together these drugs are known as phenethylamine
  hallucinogens

23
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

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• 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

25

• 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 5-HT2A 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

26
14.7 Blockade of psilocybin-induced visual
illusions and hallucinations
27

• 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

28

• 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

29
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
  5-HT2A receptors after repeated LSD exposure
• Takes 3 or 4 days for tolerance to go away

30
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.

31
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

32
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

33

• 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

34
Addiction?

• 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
• Doesnt 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
• Comatose state
• Vomiting
• Hyperthermia
• Light gastric bleeding
• Respiratory problems
• They all survived without residual effects

35

• 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

36
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
• 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

37

• 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 disorientationto
  hallucinations, severe agitation, and violence.
• Clinical use of PCP was terminated in 1965

38

• PCP became a more popular illicit drug in 1967.
• AKA Angel dust hog
• Never was as popular as marijuana or even cocaine
  or heroin

39

• 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

40
Route of administration

• PCP is generally obtained in powder form
• Can be ingested by any common route
• Orally
• Intranasally
• IV
• IM
• Smoked
• Applied as a liquid to a cigarette

41
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.

42

• 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

43
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

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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

46
PCP and Ketamines 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

47
14.12 Self-administration of PCP into the
nucleus accumbens shell by rats (Part 1)
48
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

49

• 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

50
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

51

• 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

52
14.13 Ketamine administration produces a
dose-dependent increase in psychotic-like symptoms