HALLUCINOGENS: Flashcards
can be assigned to one of 5 groups based on their structure:
1) acetylcholine-like;
2) serotonin-like;
3) catecholamine-like;
4) glutamate-like; and
5) opiate-like
pharmacodynamics
experience elicited by
a) blocking cholinergic synapses
b) stimulating 5-HT2A synapses;
c) blocking NMDA synapses; or
d) facilitating kappa-opiate synapses.
Anticholinergics
moderate hallucinatory effects
many unwanted side effects;
not regulated by DEA
scopolamine is classic drug and does what
Anticholinergics
blocks m-ACh receptors;
found in motion-sickness patches
peripherally, produces dry mouth, blurred vision, increased heart rate
found naturally in belladonna (nightshade); ingested as a beauty aid in ancient times (causes pupil dilation and skin flushing)
scopolamine pharmakinetics
usually ingested orally; very fat soluble so can be absorbed through skin
metabolized by the liver; excreted in urine
scopolamine doses
ED50 of about 0.5 mg dose; LD 50 of about 4 mg dose ~ TI of about 8
scopolamine abuse facts
low abuse potential; effects are quite aversive as hallucinatory doses also
produce profound amnesia; fatigue; dreamless sleep and a potent loss of attention
not sensory-expanding, but rather sensory constricting with perceptions dominated by hallucinations out of any context
a “classic ingredient” in witch’s
brew; may be reason for perceptions of flying and magical happenings
5-HT Agonists
catecholamine-like drugs: mescaline or MDMA
serotonin-like drugs: LSD or psilocybin
most well-known hallucinogenic substances
common mechanism of action is as a 5-HT2A agonist
Mescaline
5-HT Agonists
catecholamine-like
least potent; bitter tasting drug often induces vomiting
ingested orally at doses of 200-500 mg/person (roughly 5 mg/kg
water soluble but not very lipid soluble; takes 1-2 hr to reach peak CNS levels;
hallucination occur 2-3 hr after ingestion
structurally similar to norepinephrine
not metabolized; effects last until drug
is cleared from the system; has a ½ life of about 6 hours
hallucinations are often gentle, colorful imagery and patterns; “things make sense”
SPECT reveals a “hyperfrontal” state,
especially in the right frontal (spatial, emotional, non-language, imagery) lobe
Psilocybin
structurally like 5-HT (serotonin)
taken orally at a dose of 0.25 mg/kg; effects last 2-6 hr
water soluble; absorption in all body tissues, including mouth
metabolized to psilocin (active ingredient) in the liver; fu
her breakdown by MAO to
inactive form
TI is quite high; LD50 for humans is unknown, but in lab species LD50 = 280 mg/kg and ED50 = 0.25 mg/kg, TI = 1000)
more intense hallucinations; changes in time/space perception, color perception, disconnection/hyperconnection with a sense of self and the universe
produces a hyperfrontal state
LSD
synthetic; based on ergot alkaloid structure; similar structurally to 5-HT
potent; normal dose is barely visible
taken orally at a dose of 25-300 micrograms
readily absorbed; peak brain levels in about 1-3 hr
metabolized by the liver; usually lasts 6-8 hr
TI is quite high; LD50 = 1.4 mg/kg and
ED50 = 0.005 mg/kg, TI = 280
very intense hallucinogen; slowing of time, changes in space perception, color perception; hallucinations of objects possible or not possible; synesthesia common; also induces a hyperfrontal state
Why 5-HT2A agonists have hallucinatory effects is not clear; competing but likely related hypotheses include:
A) Enhanced Locus Coeruleus Activity (Aghajanian and Marek):
- LC is located in the pons; reciprocal connectivity with all sensory systems
- LC is the sole source of NE to the forebrain; release enhances response of postsynaptic neurons to glutamatergic excitation
- idea is that hallucinogens inhibit basal LC activity but make these cells more responsive to sensory inputs
- thus, in the presence of sensory stimuli LC cells are more active, enhancing the activity of sensory systems
B) Enhanced Cortico-Striatal-Thalamic Activity (Vollenweider and Geyer)
-hallucinogens effective by increasing synaptic activity between thalamus (sensory inputs), cortical regions (especially areas like frontal association areas), and striatum (related to learning/memory/integration of sensations for selection/initiation of movement sequences)
-increased activity may be reflected in the increased activation of cortical neurons
reported by Aghajanian and Marek…
NMDA Glutamate Antagonists…
PCP/Ketamine (Dissociative anesthetics)
antagonists at NMDA-glutamate receptors
NMDA receptors underlie much synaptic plasticity, are found throughout the nervous system including areas such as the cortex, the LC, the thalamus, and the striatum
PCP also a D-2 agonist;
may contribute to its psychosis-inducing effects
PCP
antagonist at NMDA-glutamate receptors
also a D-2 agonist;
usually smoked, but can be taken orally or injected
when smoked, peak effects occur w/in 15 min; fat soluble and demonstrates considerable depot binding
ED50 for PCP of about 1 mg/kg dose; LD50 (due to renal failure or hyperthermia) occurs at about 70 mg/kg so TI is fairly high
metabolized in liver
PCP has a longer half-life than ketamine (about 18 hr) (relatively long time for recreational drug);
mostly excreted in urine
produces feelings of detachment from body; floating; inability to focus on events; altered somatosensations; feelings of cosmic contact alters frontal lobe function,
produces a hypofrontal state
Ketamine
antagonist at NMDA-glutamate receptors
taken orally, snorted or injected
lipid and water soluble; shorter lasting effects
ED50 of about 1 mg/kg; no known LD50 due to ketamine alone
PCP has a longer half-life than ketamine (about 18 hr) (relatively long time for recreational drug);
mostly excreted in urine
produces feelings of detachment from body; floating; inability to focus on events; altered somatosensations; feelings of cosmic contact alters frontal lobe function,
produces a hypofrontal state
