Transcript gangrenous ergotism

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produce visual hallucinations and out of body
experiences
alterations in cortical functioning
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Also affect mood, thinking and
physiologicalprocesses
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At least 90 different species of plant and many
synthetic agents can produce these effects
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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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ANTICHOLINERGIC
◦ Scopolamine
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CATECHOLAMINERGIC
◦ Mescaline
◦ DOM, MDA, DMA, MDMA (ecstasy), etc
◦ Myristicin, elemicin
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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
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OPIOID KAPPA R AG
◦ Salvinorin A
 from Salvia plants
Serotonin-like drugs –
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includes lysergic acid diethylamide (LSD)
psilocybin, psilocin
dimethyltryptamine (DMT)
bufotenine
5HT acting psychedelics produce characteristic
syndrome
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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 doesn’t 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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Grew on rye (and some other grain) when
weather conditions were right
Types of ergot poisoning
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convulsive
◦ characterized by twisting and contorting body in
pain, trembling and shaking, muscle spasms,
confusions, seizures, delusions and hallucinations
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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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Joan of Arc
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Saint Anthony’s 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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Joan of Arc
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Saint Anthony’s Fire
◦ dreaded illness in the Middle Ages
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LSD –
◦ during mid 1960’s – 1970’s – LSD –
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History
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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)
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most potent drug in existence
◦ 10 – 300 ug
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Uses of LSD – 1953 - 1966
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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 1960’s
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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)
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Pharmacokinetics
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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◦
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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
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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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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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
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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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mescaline identified in 1918
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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
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MDMA – Ecstasymethlenedioxymethamphetamine
◦ potent and selective serotonin neurotoxin
◦ neurotoxic – issues re raves
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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 don’t usually try again
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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
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Recreational Use of PCP
◦ early 1970’s – PCP crystals sprinkled onto
oregano, parsley, etc and sold as marijuana
◦ can be made inexpensively and relatively easily
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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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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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from salvia plant (magic mint, diviner’s sage,
Sally-d)
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potato family contains all naturally
occurring agents in this category
◦ atropine, scopolamine
◦ atropine – belladonna – active ingredient in
deadly nightshade.
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ACh antagonist –
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comes from belladona (Deadly nightshade)
Jamestown weed, jimsonweed, stinkweed,
devil’s apple, moonflower, mandrake
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scopolamine containing plants have been
used and misused for centuries
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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 LotsofPreclinical data reduces selfadministration 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