Psychedelic Drugs

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Psychedelic Drugs
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Psychedelic Drugs

• produce visual hallucinations and out of body
  experiences
• alterations in cortical functioning
• Also affect mood, thinking and physiologicalproces
  ses
• At least 90 different species of plant and many
  synthetic agents can produce these effects
• Distinguish them by the NT system that they work
  on (primarily)

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• many occur in nature other newer ones are
  synthetically produced
• Prior to 1960 (or so) these were primarily
  restricted to religious rituals and most people
  were not even really aware of them

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• Most psychedelics resemble one of 4 NT
• ACh, catecholamines (NE, DA) and 5HT

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Classification of Psychedelic drugs

• ANTICHOLINERGIC
• Scopolamine
• CATECHOLAMINERGIC
• Mescaline
• DOM, MDA, DMA, MDMA (ecstasy), etc
• Myristicin, elemicin
• 5HT like
• Lysergic acid diethylamide (LSD)
• Dimethyltryptamine (DMT)
• Psilocybin, psilocin, bufotenine, Ololiuqui,etc

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• GLUTAMINERGIC NMDAR ANT
• Phencyclidine (Sernyl) (PCP)
• Ketamine (Ketalar)
• Dextromethorphan
• OPIOID KAPPA R AG
• Salvinorin A
• from Salvia plants

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hallucinogens

• Serotonin-like drugs
• includes lysergic acid diethylamide (LSD)
• psilocybin, psilocin
• dimethyltryptamine (DMT)
• bufotenine
• 5HT acting psychedelics produce characteristic
  syndrome
• disturbances in thinking, illusions, elementary
  and complex visual hallucinations

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• believe that these psychedelics interact with
  5-HT2A receptors
• LSD agonist
• DMT, bufotenine partial agonist
• ?? why doesnt 5HT have psychotomimetic effects?
  What about SSRIs?

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• naturally occurring compounds exist that resemble
  the indole ring
• investigating therapeutic use of compounds
  obtained from ergot fungus
• LSD belongs to class of agents called ergot
  alkaloids

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Ergot fungus

• Grew on rye (and some other grain) when weather
  conditions were right
• Types of ergot poisoning

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2 types of ergot poisoning

• convulsive
• characterized by twisting and contorting body in
  pain, trembling and shaking, muscle spasms,
  confusions, seizures, delusions and
  hallucinations
• gangrenous ergotism
• Due to decreased blood flow, infections occur in
  the extremities, accompanied by burning pain and
  loss of extremities.

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• explanation for witch trials.

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Other possible examples of ergot poisoning

• Joan of Arc
• Saint Anthonys Fire

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• On August 15, 1951 one in twenty of the 4000
  inhabitants of a village in France called Pont
  Saint Esprit (Bridge of the Holy Spirit) went
  mad. They had hallucinations, writhed in agony in
  their beds, vomited, ran crazily in the streets
  and suffered terrible burning sensations in their
  limbs.

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Other possible examples of ergot poisoning

• Joan of Arc
• Saint Anthonys Fire
• dreaded illness in the Middle Ages

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• LSD
• during mid 1960s 1970s LSD
• History
• synthesized in 1938
• Albert Hoffman (Sandoz)- swiss chemist
• looking for possible therapeutic uses of ergot
  fungus
• early animal studies not much
• first human experience 1943 although arguments
  can be made for a much earlier time

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• LSD 25 had strong uterine effect and animals
  became stuporous but restless
• nothing of special interest set back on shelf
• 5 years later made new batch and must have
  gotten tiny amount on fingers
• tried it again under a more controlled condition
  using a 0.25 mg dose (10X the dose for most to
  show an effect)
• most potent drug in existence
• 10 300 ug

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• Uses of LSD 1953 - 1966
• LSD used as adjunct to psychotherapy
• possible treatment for alcoholics
• treating cancer patients
• possible truth serum

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• 1966- Sandoz recalled LSD and withdrew
  sponsorship for work with LSD
• NIMH stopped LSD research (in house) in 1968
  stopped funding in 1974
• NIAAA stopped supporting psychedelic research
  in 1975

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• Recreational Use of LSD
• early to mid 1960s
• Pharmacology of LSD
• drug is odorless, colorless, tasteless
• extremely potent (25 100 ug) but no OD death
  reported in humans
• rats behavioral effects at 0.04 mg/kg and LD50
  16 mg/kg (400X the behaviorally effective dose)
• Pharmacokinetics
• absorption rapid oral route most common
• ½ life 3 hrs
• Effect usually lasts 8-12 hours
• metabolized in liver

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• tolerance develops very rapidly
• recovery is also usually rapid (so weekly use of
  same dose is possible)
• Cross tolerance LSD with psilocybin, mescaline
• Sympathomimetic (activates sympathetic NS) and so
  autonomic signs are often first to appear
• dilated pupils, elevated temperature, BP and
  salivation

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• LSD experience-
• mostly visual/perceptual changes
• altered sense of time
• synethesia mixing of senses
• depersonalization
• typical lasts 6 9 hours
• Adverse Reactions
• panic reaction
• flashbacks
• quite variable and unpredictable

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Bufo Marinus, also known as the cane toad,
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• skin and glandular secretions
• toad secretions have been used since ancient
  time

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• Psilocybin
• long history in religious and ceremonial use
• indole isolated by Abby Hoffman and then
  synthesized

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• Morning Glory Seeds

• Hoffmann analyzed seeds
• found several active alkaloids as well as
  d-lysergic acid amide
• dangers pesticides, substances coated on seeds
  in US coatings on seeds can cause nausea,
  vomiting, headaches, increased BP, probably need
  100s for species common in US

Heavenly Blue
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Catecholaminelike Psychedelics

• NE and DA receptors important site of action for
  a large group of psychedelic drugs structurally
  similar to catechol NT and amph
• differ from nt by one or more methoxy group
  (-OCH3)
• exert amphetaminelike psychostimulant actioons
  can enhance energy, endurance, sociability and
  sexual arousal
• psychedelic actions probably due to augmentation
  of 5HT neurotransmissions (5HT2A)

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Mescaline

• Peyote common plant in southwest US and Mexico
• Spineless cactus with small crown or button

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• mescal buttons (not mescal liquour from agave
  cactus, mescal beans)
• dates back 5000 or more years
• Aztecs
• used in spiritual ceremonies (Native American
  Church)
• Members of Native American Church exempt from
  federal criminal penalities for religious use
  (predates CSA)

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Pharmacological Effects

• mescaline identified in 1918
• pharmacokinetics
• mescaline rapidly absorbed orally
• levels increased in brain 1-2 hrs
• acute psychotomimetic state 3.5 4 hrs
• effects can persist for 10 hrs
• does not appear to be metabolized
• imaging studies hyperfrontal pattern of
  activity (right hemisphere)

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• Synthetic amphetamine derivatives
• large group of synthetic hallucinogens chemically
  related to amphetamines
• structurally related to mescaline and
  methamphetamine
• exs. DOM dimethyoxymethamphetamine
• 100X more potent than mescaline (but less potent
  than LSD)
• high incidence of OD use not common toxic
• MDMA Ecstasy- methlenedioxymethamphetamine
• potent and selective serotonin neurotoxin
• neurotoxic issues re raves

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myristicin and elemicin

• nutmeg and mace
• common household spices
• ingestion of large amounts confusion
  disorientation, impending doom, depersonalization
• structural resemblance to mescaline
• many unpleasant side effects including vomiting,
  nausea and tremors
• if people try it once they dont usually try
  again

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glutaminergic NMDAR ant

• PCP (phencyclidine)
• developed as an IV anesthetic- Sernyl Parke
  Davis
• monkey studies suggested that it was a good
  analgesic but did not produce muscle relaxation
  OR sleep
• a dissociative anesthetic
• several patients were unmanageable as they
  emerged from the anesthetic
• studies showed patients becoming angry or
  uncooperative reduction in sensitivity to pain
  in combination could contribute to violent
  behavior

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• PCP (phencyclidine)
• few reports of intense visual experiences and
  many more reports of body image changes
• reports of disorganized thinking, suspiciousness
  and lack of cooperation
• Recreational Use of PCP
• early 1970s PCP crystals sprinkled onto
  oregano, parsley, etc and sold as marijuana
• can be made inexpensively and relatively easily
• PCP receptor discovered in 1979
• appears to antagonize GLU
• endogenous ligand as yet unknown

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• Other PCP like drugs
• Ketamine
• related veterinary product

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• Other PCP like drugs
• Ketamine
• related veterinary product
• 1999 widespread reports of ketamine abuse
  resulted in ketamine receiving Schedule III
  designation
• not as strong an effect as PCP

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dextromethorphan

• an analgesic and a drug of abuse
• common ingredient in more than 140 OTC cough
  suppressants
• high doses produce hallucinations
• highest age group for abuse potential -

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Salvinorin A

• from salvia plant (magic mint, diviners sage,
  Sally-d)

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anticholinergic hallucinogens

• potato family contains all naturally occurring
  agents in this category
• atropine, scopolamine
• atropine belladonna active ingredient in
  deadly nightshade.

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scopolamine

• ACh antagonist
• comes from belladona (Deadly nightshade)
• Jamestown weed, jimsonweed, stinkweed, devils
  apple, moonflower, mandrake
• scopolamine containing plants have been used and
  misused for centuries
• Professional and amateur poisoners used deadly
  nightshade as a source of poison

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Ibogaine - psychoactive indole alkaloid from
roots of Tabernanthe iboga Howard Lotsof-
Preclinical data reduces self- administration of
both cocaine and morphine, as well as attenuates
symptoms of morphine WD
mechanism of anti-addictive action of ibogaine
not well defined
NMDA R antagonist kappa agonist mAChR
activity has hallucinogenic effects in humans