Chapter 12: Psychedelic Drugs
LSD moderate dose range capable of achieving significantly altered state of consciousness
0.075 to 0.15 mg (an amount of LSD the size of an aspirin tablet would 3,000 people)
Two mechanisms through which acute administration of MDMA alters serotonin neurotransmission at axon terminals:
1) MDMA inhibits serotonin transportation into synaptic storage vesicles. In doing so, MDMA prevents serotonin storage and permits serotonin to escape into the synaptic cleft. 2) MDMA causes the reversal of serotonin reuptake transporters. By doing this, MDMA expels any unstirred serotonin into the synaptic cleft MDMA produces in increase in extracellular brain serotonin levels through these two mechanisms. These increased serotonin levels in turn to increased activation of serotonin receptors
Phencyclidine effects of actions of dopamine system:
1) dopamine membrane transporter for reuptake is inhibited and causes an increase in dopamine outside the neuron, which facilitates activation of dopamine receptors 2) partial agonist for dopamine D2 receptors
Phencyclidine and similar dissociative function as antagonists for...
1) glutamate NMDA* receptors - NMDA receptors are inotropic and contain binding sites for many substances on the ion channel's subunits - when phencyclidine binds to this site, it prevents positively charged ions from entering the channel which interferes with long-term potentiation long-term potentiation: a form of synaptic plasticity for learning and memory - depends on postsynaptic AMPA** and NMDA glutamate receptors and the neurotransmitter glutamate - occurs when the membrane depolarizes sufficiently to repel the Mg+² ion from the channel (*N-methyl-D-aspartate) (**α-amino-3hydroxy-5methyl-4-isoxazole proprionic acid)
Phencyclidine causes enhanced serotonin neurotransmission through two mechanisms:
1) inhibition of the serotonin reuptake inhibitor 2) agonist at 5-HT₂a receptors
Three types of phencyclidine administration: With the powder form:
1) intravenous injection 2) inhalation 3) insufflation insufflate, intravenously inject, or smoke
Psychoactive effects onset time Smoking: Insufflation: Absorption elimination half-life:
1) leads to psychoactive effects within 1 to 5 minutes and reaches peak effects within 5 to 30 minutes 2) achieves drug effects within 30 secs to 1 minute 3) 18 hours, but it can be as long as 51 hours
three primary dissociative anesthetics
1) phencyclidine (PCP); "PeaCe Pill" or the powder form "angel dust" 2) Ketamine; "Special K or K" 3) Dizocilpine; "MK-801" (primarily used for research purposes)
What two things did Hofmann learn from his self experiment?
1. Dosage, he took only one quarter milligram of LSD, & it had a surprisingly strong effect 2. LSD is a powerful hallucinogenic drug (his second "trip" lasted 6 hours)
The neurotransmission effects of LSD impact many sensory-processing systems in the brain such as...
1. The Visual Cortex: LSD activates both 5-HT₁A and 5-HT₂a receptors, modifies any number of visual processes (such as model object completion), and weakens N170 waveform amplitudes in specific areas of the visual cortex which correlated with overall decreased activity in the occipital lobe. 2. Alter functioning in the locus coeruleus: increases the activity of both glutamate and GABA neurons, and causes normally supressed sensory information from the locus coeruleus to become more refined and salient. 3. Prefrontal Cortex: causes increased glutamate release which increases activity in the prefrontal cortex (the central integration area for processed sensory information) and enhances activity in the temporomedial cortex (region involved in complex visual processing) *These enhanced activity levels in the prefrontal cortex and temporomedial cortex also occurred while participants experienced visual hallucinations*
three classifications of psychedelic drugs
1. hallucinogens 2. mixed stimulant-psychedelics 3. dissociative anesthetics
Fewer than ____ ___________ individuals 12 and older had used a hallucinogen within the previous 12 months.LSD was used by fewer than ___________ U.S. individuals 12 and older
1.3 million; 340,000
In surveys conducted on undergraduate college students, approximately ___% had used LSD, and nearly ____% had use hallucinogenic mushrooms
15%; 25%
MDMA was discovered when and by who?
1914 by Merck
Cells in the liver metabolize LSD and produce what?
2-oxo-3-hydroxy-LSD
LSD functions as a receptor agonist with high binding affinity for what?
5-HT₁a, 5-HT₂a, 5-HT₆, and 5-HT₇ receptors
What is the serotonin metabolite?
5-hydroxyindolacetic acid (5-HIAA)
peak absorption through oral administration of LSD
60 minutes
Who accidentally discovered LSD? Where?
Albert Hofmann; Sandoz Laboratories in 1943
Who published the first paper for LSD in psychiatric patients?
Antony Busch and Warren Johnson in 1950
Phencyclidine's actions on other neurotransmitter systems:
At higher concentrations... - functions as a noncompetitive antagonist for nicotinic cholinergic receptors at neuromuscular junctions (causes muscles to contract)and at ganglia in the peripheral nervous system (alters sympathetic and parasympathetic nervous system activity) - antagonize muscarinic receptors in the central and autonomic nervous systems - activate opioid kappa receptors
What is the psychedelic compound found in over-the-counter cough syrups such as Robitussin DM?
Detromethorphan
Why is MDMA called an empathogen?
Empathogen is derived from the tendency of MDMA to induce friendliness, closeness with others, and greater insight into one's thoughts and emotions
What effect does sustained MDMA use have on serotonin neurons?
Heavy sustained MDMA use destroys serotonin neurons
Hallucinogens include:
LSD, psilocybin, mescaline, and dimethyltryptamine
How does a dissociative anesthetic drug such as phencyclidine interfere with long-term potentiation?
Like Mg+², phencyclidine binds to a site with the NMDA channel, which prevents ions from entering the neuron through NMDA channel. This action weakens the postsynaptic neurons response to the presynaptic neuron
_______________, ______________, and _____________ increased ratings of friendliness and talkativeness. Each drug also increased a sense of improved cognition.
MDMA, d-amphetamine, and mCPP
At which doses do the anesthetic effects of a dissociative anesthetic drug occur?
Numbness occurs at low doses and become more pronounced at moderate doses
Decencies in the CYP2D6 enzyme lead to accumulation of MDMA. Accumulated MDMA leads to what? Certain SSRIs such as fluoxetine (Prozac) inhibit ________ ________. These actions inhibit MDMA metabolism, leading to effects similar to those with inherent ___________ ____________.
Prolonged drug effects and an increased probability of adverse effects occurring at low to moderate doses CYP2D6 activity; CYP2D6 deficiencies
What is the main psychoactive constituent in hallucinogenic mushrooms that belong?
Psilocybin (belong to the genus Psilocybe)
Although MDMA was developed decades earlier, who popularized MDMA in the 1970s?
Psychopharmacologist Alexander Shulgin
Which comanche chief stated that the Great Spirit Within communicated with him through a peyote experience to make peace with the white man and seek spiritual communion and wisdom?
Quanah Parker
Although Salvinorin A elicits hallucinogenic effects through activating 5-HT₂a receptors, what other pharmacological action might contribute to the compound's psychedelic effects?
Salvinorin A also functions as an agonist for kappa opioid receptors
What are scopolamine and atropine unattractive recreational psychedelic substances?
Scopolamine, atropina, and other muscarinic receptor antagonists exhibit confusion and delusional thinking. In particular, these drugs exhibit profound inhibition of memory
Who banned hallucinogenic practices?
Spanish conquistadors
The term phencyclidine often incorrectly refers to other drugs such as
THC, cannabidiol, mescaline, and LSD
Although LSD activates many types of serotonin receptors, which receptor is most associated with visual hallucinations?
The 5-HT₂a receptor
How do the reinforcing effects of dissociative anesthetics compare to the hallucinogen LSD?
Unlike LSD, animals learn to self-administer dissociative anesthetics. In addition, humans report enjoying the dissociative anesthetic drug ketamine. Overall, dissociative anesthetics appear to exhibit greater reinforcing effects than LSD.
What is a partial agonist?
a drug that binds to a receptor but has a weaker ability, compared to full agonists, for activating the receptor
What can affect LSD's subjective effects?
a person's expectations and previous experiences
hypersuggestibility
a state that can jeopardize reality testing
lysergic acid diethylamide (LSD) street names
acid, window pane, and blotter
psilocin
active metabolite of Psilocybin; a hallucinogenic substance that likely accounts for most of Psilocybin's effects
LSD's elimination half-life?
approximately 3 hours, which facilitates pharmacological effects lasting as long as 8 hours
Psychedelic drugs
drugs that induce a reality-altering experience consisting of hallucinations, sensory distortions, or delusions
Both AMPA & NMDA produce _______ postsynaptic potentials by allowing the entry of positively charged ions such as NA+
excitatory
Excitatory postsynaptic potentials refers to
excitatory input from other neurons that result in membrane depolarization
synesthesia
experiencing sensory stimuli in an incorrect sensory modality associated with a good trip
What is the difference between phencyclidine's psychedelic effects compared to LSD and MDMA?
feeling of disconnectedness from the body and research suggests that it produces reinforcing effects (this property led to classifying phencyclidine and other drugs as dissociative anesthetics)
What is the key psychedelic effect of dissociative anesthetics?
feelings of disconnection from the body
flashback vs hallucinogen persisting perception disorder
flashback- random, short, and non distressing memory of a previous hallucinogenic experience hppd- recurring, lengthy, and unpleasant memory from a previous hallucinogenic experience
Why did aztecs use peyote?
for religious ceremonies and because peyote granted perceptions of great insight and altered realities which provided the integral experience of communicating with gods
Where is the hallucinogen dimethyltryptamine (DMT) found?
found in Mimosa hostilis, Virola calophylla, and other hallucinogenic South American plants
How did Hofmann happen upon his discovery?
he was synthesizing derivatives from ergot, a fungus already known to elicit mild hallucinogenic effects
hallucinogens
large class of psychedelic drugs that produce hallucinations as their main pharmacological effects
Rave
large organized party held in a dance club or warehouse where electronic dance music is played with a light show MDMA and other psychedelic drugs are frequently used in raves
MDMA is metabolized where and by what?
liver; CYP2D6 enzymes and to a lesser extent by other enzymes such as CYP1A2
What are the key differences in pharmacological actions between low and high MDMA doses?
lower doses: primarily enhance serotonin neurotransmission higher doses: primarily enhance both serotonin and dopamine neurotransmission
What is LSD synthesized from?
lysergic acid
What drug is the most representative of the hallucinogen class?
lysergic acid diethylamide (LSD)
At moderate doses, phencyclidine impairs...
memory and elicits depressant effects (likely related to disruption of long-term potentiation)
Which effects of dissociative anesthetic drugs relate to interference of long-term potentiation?
memory disruptive effects
CYP1A2 converts MDMA to what?
methylenedioxyethamphetamine (MDA)
MDMA (Ecstasy)
mixed stimulant psychedelic drug; chemically, 3, 4-methylenedioxyethamphetamine
phencyclidine (PCP)
most abused drug among the dissociative anesthetics; also known as "angel dust"
atropine
muscarinic receptor antagonist that produces true visual hallucinations, delusional thinking, and disorientation about time and place
scopolamine
muscarinic receptor antagonist that produces true visual hallucinations, delusional thinking, and disorientation about time and place
What do the primary adverse effects of hallucinogens consist of?
negative subjective effects, such as those experienced during a bad trip
dextromethorphan
opioid cough suppressant found in many over-the-counter cold medications
After ______ administration, psilocybin converts to its active metabolite _________
oral; psilocin
MDMA preferred administration route: peak blood plasma levels time: elimination half-life:
orally; 2 hours; 9 hours
trip
overall hallucinogenic experience
pseudo-hallucination
perception of images or sounds that ARE REAL -LSD doses cause distorted, waiving, or kaleidoscopic forms of real images in visual fields -associated with a "good" trip
true hallucination
perception of images or sounds that are NOT real -can occur with LSD but are rare -associated with a "bad" trip
model object completion
perception of object boundaries inferred from incomplete representations of the object
Where is the hallucinogen mescaline found? How is it obtained?
peyote (a small, spineless cactus native to southern North America) obtained by chewing disk-shaped buttons within the cactus crown
For close to half of those college students using MDMA, ___________ use was common
polydrug
LSD is _______, with effective amounts beginning at only ______
potent; 0.025 mg
Like MDMA, MDA exhibits...
psychedelic drug effects Its users thus experience specific MDMA effects and then, after metabolic transformation, effects elicited by MDA as well
What did primitive cultures use hallucinogenic plants for?
psychic medicines to treat maladies, communicate with gods, and perform magic
salvinorin A
psychoactive constituent of the psychedelic plant Salvia divinorum
The subjective effects of MDMA relate to both ___________ and ___________ drugs
psycostimulants and hallucinogenic
MDMA's physiological effects
resemble those of psychostimulant drugs such as amphetamines at higher doses BUT few at lower doses HOWEVER both high and low doses elicit significant subjective effects
Phencyclidine and related dissociative anesthetics also elicit what type of impairments?
schizophrenia-like cognitive impairments
Dissociative anesthetics
sedative, pain-relieving drugs that produce feelings of disconnectedness from the body and have depressant and stimulant effects
What does LSD activate in particular?
serotonin receptors located postsynaptically on other neurotransmitter neurons, such as glutamate and GABA neurons
The chemical structure of LSD resembles what? What does this allow?
serotonin's chemical structure; this allows LSD to act on serotonin receptors
Phencyclidine affects
serotonin, dopamine, acetycholine, and glutamate neurotransmission
MDMA metabolism ________ ________ over time
slows down
LSD and many other serotonin-like hallucinogens primarily elicit what type of pharmacological effects?
subjective
mixed stimulant psychedelic drugs
substances that exhibit both psychostimulant and hallucinatory effects as their primary pharmacological effects ex. MDMA or Ecstasy, AMT, & 5-MeO-DIPT
Psychostimulant drugs activate the _________ nervous system
sympathetic
entactogen
term meaning "touching within"; usually in reference to mixed stimulant psychedelic drugs
empathogen
term referring to enhanced empathy; usually in reference to mixed stimulant psychedelic drugs
Aside from recreation, what were the other historical uses of LSD?
tested by the U.S. military to aid in prisoner interrogation and to use as a chemical weapon. the drug was also used in psychotherapy
What is unique about the hallucinogen dimethyltryptamine (DMT)?
the body produces smalls amounts of DMT, although the function of endogenous DMT remains largely unknown
Cognitive deficits occur from repeated MDMA use. These deficits particularly impact what?
verbal and working memory
MDMA's effects on dopamine axonal terminals are _________ than its effects on serotonin axonal terminals
weaker
(Men or women) exhibit a greater sensitivity to nearly every measure of MDMA's effects
women
Psychedelic
"mind-expanding"
