Psychedelic/Hallucinogens- Chpt 12

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Psychedelic/Hallucinogens- Chpt 12

• Primary effect is to produce perceptual changes
  hallucinations
• Can influence several sensory systems, perception
  of time, space events

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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

DMT
5-HT
Mescaline
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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

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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

• Depicts the typical dose range taken by
  recreational users (psilocybin is most potent and
  mescaline is the least)

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
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Physiological Responses

• Activation of the sympathetic nervous system
• Pupil dilation, small increases in heart rate,
  body temp and blood pressure
• Dizziness, nausea, and vomiting

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Psychological Effects

• State of intoxication usually called a trip
• Trip can be divided into four stages
• Other psychological effects include
  depersonalization, anxious or fearful state,
  disruption of logical thought.
• Good trip versus Bad trip depends on dose,
  users personality, expectations, previous
  experiences, physical and social settings

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
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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?

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Experimental receptor study

• Vollenweider (1998)
• Administration of antagonists
• Risperidone, Ketanserin (5-HT2A D2 DA)
• Decreased drug-induced visual illusions/hallucinat
  ions
• 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

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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 phenyl-
• ethylamine drugs
• Only receptors in common
• 5-HT2A, 5-HT2C

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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

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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

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SerotonergicPsychdelics
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Serotonergic Hallucinogens

• Lysergic acid diethylamide (LSD, Acid)
• Psilocybin-Psilocybe mushrooms-Shrooms
• Mescaline-Peyote cactus
• Ergine-Morning glory
• Harmaline-Ayahuasca,Yage

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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

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Aldous Huxley
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Albert Hofmann-Discovered LSD
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Timothy Leary and Ken Kesey
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Doses of Acid
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Effects of LSD etc...

• Sympathomimetic
• Visual hallucinations

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Visual Hallucinations

• Enhanced color perception
• Flickering of the visual field
• Perception of motion
• Synesthesia
• Form constants

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Form Constants

• Lattice Pattern

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Form Constants

• Lattice Pattern
• Tunnel/Vortex

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Form Constants

• Lattice Pattern
• Tunnel/Vortex
• Spiral Explosion

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Visual Hallucinations

• Enhanced color perception
• Flickering of the visual field
• Perception of motion
• Synesthesia
• Form constants

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Form Constants

• Lattice Pattern
• Tunnel/Vortex
• Spiral Explosion

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Effects of LSD etc...

• Sympathomimetic
• Visual hallucinations
• Altered consciousness
• Tolerance (but no dependence)

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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

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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?
• MythCauses of flashbacks unclear

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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

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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

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LSD in the USA

• Spread through country with huge publicity until
  peak 1968 to 1972
• Schedule I in 1968
• Stuffy politicians didnt know what to do because
  LSD was used by white, middle to upper class,
  college students
• Early 1990s - LSD came back

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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

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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
•  

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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 experimenters previous behavior
• warm and supportive or suspicious and
  nonsupportive

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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

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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

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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

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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

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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

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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

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Psilocybe Mushrooms-psilocybin
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Psilocybe Mushrooms-psilocybin
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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

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Psilocybin, DMT, 5-MeO-DMT (contd)

• 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
  ß-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

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DMT

• Dimethyltriptamine
• 5-HT2A agonist
• Alkaloid
• Often smoked
• Main ingredient in Ayahuasca
• Same effects as LSD

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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

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Ololiuqui

• Substance found in morning glory seeds
• Similar to LSD
• Significant nausea, vomiting and cramping

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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

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Catecholamine-likePsychedelics
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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

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Peyote cactus-mescaline
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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)

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Peyote cactus-mescaline
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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

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Ecstasy

• MDMA (methylene-dioxy-methamphetamine)
• Synthesized in 1912
• Structurally related to amphetamines
• Sympathomimetic
• Weak in altering perceptual functions
• But strong effects on emotions - empathogen
• Used in combo with psychotherapy
• Of interest http//www.biopsychiatry.com/intervie
  w/index.html

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Methylated Amphetamines

• Methylenedioxymethamphetamine (MDMA, Ecstasy,
  XTC)
• Methylenedioxyamphetamine (MDA)

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Ecstasy (MDMA) Psychological Effects

• Increased alertness, arousal, insomnia--stimulant
  effects
• Euphoria, increased emotional warmth
• Increased empathy and insight?
• Hallucinogenic effects are largely absent

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Ecstasy (MDMA) Physiological Effects

• Sympathomimetic
• Bruxism Trismusteeth grinding jaw clenching
  (pacifiers)
• Dehydration/Overhydration
• Hyperthermia
• Tachycardia
• Collapse/Overdose death

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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 serotonindamage
  to serotonin neurons in nonhumans

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Ecstasy and the brainPreclinical 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?

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Ecstasy and the brainThe 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.
• Ricaurtes 2003 retraction and the fallout

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Are doses used in preclinical research too high?

• Although neurotoxic doses in non-humans (5-20
  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 nights binge and a tablet may
  contain up to 300 mg 4-5 mg/kg in an average
  person.

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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)

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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)

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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?

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Ecstasy in humans

• Morgan (2000) review Heavy users more
  depression, sleep disorders, memory problems than
  controls

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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.

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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

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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

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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

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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 userssuggests recovery after a
  period of abstinence (see also DeWin et al, 2004
  McCann et al, 2005)

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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)

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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--

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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 dataMemory? Affect?
• Clinical trial for PTSD

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Ecstasy and the brain What do we need to know?

• Animal dataDoes MDMA produce learning and memory
  deficits in rats the UNCW project
• Student investigators Laura Bullard, Miles
  Hulick, Brooke Poerstal, Becky Rayburn-Reeves,
  Andrea Robinson

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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)

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MDMA Prototype Club Drug
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Pharmacodynamics

• Monoamine neurotransmission
• increase synaptic DA and 5-HT
• blocks 5-HT transporter
• enters neuron and causes release of 5-HT

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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

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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

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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 its
  not always X or may have other drugs

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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

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MDMA MDA neurotoxicity
5-HT immunoreactive fibers in rat parietal cortex
MDA
PCA
Normal
9.9
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Squirrel monkeys 18 mo post-trtmt
Control
5-HT immuno- reactivity
Caudate
Hippocampus
Neocortex
MDMA
McCann et al. (1997)
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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)

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Designer Psychedelics

• DOM, MDA, DMA, MDE, TMA, AMT, 5MeO-DIPT
• All structurally related to mescaline and
  methamphetamine therefore MDMA.
• MDA is a metabolite of MDMA. May be responsible
  for much of the MDMA effect.

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Myristin and Elemicin

• Found in nutmeg and mace
• Structurally similar to mescaline
• Significant nausea and vomiting
• The sick usually limit use

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GlutamatergicPsychedelics

• Dissociative Anesthetics

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Anesthetic Hallucinogens

• Phencyclidine (PCP, Angel dust, Lovely)
• Ketamine (Special K)

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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 long-term

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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

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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

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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 ones body
• Visions of spiritual or supernatural beings
• Emotions ranging from euphoria to hositlity
• Dalgarno Shewan (1996)

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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

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CholinergicHallucinogens
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Anticholinergic hallucinogens

• Atropine-from the Deadly nightshade, Datura,
  Jimson weed, and Mandrake
• Scopolamine-from Datura, Jimson weed, Mandrake
  and Henbane

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Datura
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Jimson weed
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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

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Atropine Scopolamine

• 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 eye-exams.

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Anticholinergic effects

• Dry mouth, blurred vision, loss of motor control
• Dream-like trance state
• Little or no memory of experience

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Opioid Hallucinogen - Salvinorin A

• 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
• Its still legal, but not likely for long

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Salvia Divinorum

• Plant used by the Mazatec people of Southern
  Mexico Diviners sageleaves 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 supplementcurrently under DEA review