PSYCH 373 Final

psychoactive compound in marijuana

THC

oral marijuana causes

low variable plasma levels

smoking marijuana causes

high plasma levels

after smoking marijuana

blood THC levels decline rapidly
complete elimination is much slower
urine screening test can detect 2+ weeks after 1 use

CBD vs THC

similar structures
CBD has a low affinity for cannabinoid receptors, lacks intoxicating/dependence producing effects of THC

cannabinoid receptors

CB1
CB2

are cannabinoid receptors ionotropic or metabotropic

metabotropic
G protein inhibit cAMP formation, inhibit voltage-sensitive Ca2+ channels, open K+ channels

CB1 receptor effect

central nervous system (CNS)

CB2 receptor effect

immune system, bone, fat, and GI tract

where are CB1 receptors located

axon terminals
inhibit the release of many neurotransmitters

endocannabinoids

natural, marijuana-like substances produced by the body
AEA and 2AG

where are endocannabinoids made

post synaptic cell in response to an influx of Ca2+ from depolarization
retrograde signaling

endocannabinoids are very

lipid soluble

endocannabinoid 2AG is metabolized by

fatty acid amide hydrolase (FAAH) and monoacyl-glycerol lipase (MAGL)

2AG is a full agonist at

CB1 and CB2

AEA is partial or full agonist

partial agonist of CB1 and CB2

endocannabinoid signaling mechanisms

1. retrograde signaling
2. non-retrograde signaling
3. neuron-astrocyte signaling

retrograde signaling

CB1 receptors on nearby nerve terminals are activated by 2AG and inhibit Ca2+
- mediate neurotransmitter release

non-retrograde signaling

anandamide remains in postsynaptic cell and activates either a cannabinoid receptor or a TRPV1 receptor
- regulate pain processing, mood, motor function, learning and memory

neuron-astrocyte signaling

endocannabinoids activate receptors on nearby astrocytes, resulting in release of glutamate

how many cannabis users become dependent

10%

behavioral/psychosocial factors of use of marijuana

early adolescence onset of use
positive reactions to cannabis during adolescence
use to cope with negative emotions
concurrent use of tobacco
living alone
major life stressor
comorbid psychiatric disorders (ADHD)

withdrawal symptoms of marijuana

irritability, increased anxiety, depressed mood, sleep disturbances, heightened aggressiveness, decreased appetite
similar to nicotine withdrawal

four subjective stages of cannabis effects

buzz
high
stoned
come down

cannabis high can be described by

euphoria exhilaration and sense of disinhibition

being stoned can be described as

relaxation and sensory reactions like floating, enhanced visual and auditory perception, visual illusions, time passage slows

physical responses to cannabis

increased blood flow to the skin, flushing, increased heart rate, increased hunger

in marijuana smokers, blood plasma levels of THC may decline while

maximum intoxication takes effect

acute effects of cannabis

impaired verbal learning and memory
impaired working memory
impaired psychomotor function

chronic effects of cannabis

impaired verbal learning and memory
impaired attention, attentional bias
possibly impaired executive function
- depending on frequency of use and age onset

recovery function with cannabis abstinence

likely persistent effects on attention and psychomotor function
possibly persistent effects on verbal learning and memory
- insufficient and mixed evidence

repeated exposure to cannabis in rodents

changes in glutamatergic, GABAergic and dopaminergic systems
altered synapatic plasticity, dysregulated emotional and social behaviors, impaired cognitive function
deficits in prefrontal pyramidal cell dendritic development and concomitant impairment of synaptic plasticity in hippocampal-PFC circuitry

smoking marijuana can

damage lungs and cause various respiratory symptoms

synthetic cannabinoids

more potent than THC
often full rather than partial agonist at receptor site
metabolized by different biochemical pathways
lack of CBD in synthetic cannabinoids may increase risk of psychotic reactions

how is a hallucinogen defined

produces a perceptual or cognitive distortion
novel uplifting spiritual experience
produces effects without toxic delirium
many synthesized by plants or plant derived compounds

mescaline

natural hallucinogen derived from the peyote cactus buttons

psilocybin

natural hallucinogen found in certain mushrooms

dimethyltryptamine (DMT)

hallucinogenic drug found in several South American plants and sonoran desert toad

LSD

hallucinogen derived from ergot, a parasitic fungus on rye

what is the psychoactive ingredient in mushrooms

psilocin

why can't DMT be taken orally

MAO enzymes break it down through first-pass metabolism
lacks bioavailability unless smoked or snorted

AMT, Foxy and ayahuasca are

orally active synthetic DMT hallucinogens

ergot

very toxic
causes powerful contractions of the uterus and trigger labor and reduced post birth uterine hemorrhage

who discovered LSD

Albert Hoffman

what was LSD marketed for

to uncover repressed thoughts and feelings

how long does a DMT high last

30 minutes

psycholytic therapy

therapeutic method that employed LSD in low doses, gradually increasing the dose, in attempts to recover repressed memories or increase communication with the therapist

psychedelic therapy

therapeutic method that involved giving patients a single high dose of LSD to help them understand their problems by reaching a drug-induced spiritual state

what is more potent LSD or mescaline

LSD!

how long does it take LSD to take effect

30-90 minutes

how long does an LSD trip last

6-12 hours

smoked DMT trip

felt in seconds
peak in minutes
gone in an hour

LSD trip

onset
plateau
peak
"come down"

LSD experience

vivid visual hallucinations
slowing of the subjective sense of time
feelings of depersonalization
strong emotional reactions
disruption of logical thought

peak phase of LSD high

time suspended
see continuous stream of bizarre/distorted images
can be beautiful or menacing

synesthesia

crossing-over of sensations
- words have color

a good or bad LSD trip depends on

dose, individual and social factors
set and setting

can a good or bad trip be predicted

no

Altered States of Consciousness (ASC) rating scale
(hallucinogen rating scale)

1. oceanic boundlessness
2. ego-disintegration anxiety
3. visionary restructuring
4. reduced vigilance
5. auditory alterations

LSD physical effects

activates sympathetic nervous system
pupil dilation, minimal increase in heart rate, blood pressure and body temperature changes

peyote and mushrooms can cause

dizziness, nausea, vomiting

serotonin-like hallucinogens

LSD, psilocybin/psilocin, DMT

catecholamine-like hallucinogens

mescaline/peyote
structurally similar to NE and amphetamine

LSD has a high affinity for

8 different 5HT receptor subtypes

what kind of receptor agonist or antagonist is LSD

5HT2A receptor agaonist

why is LSD so potent and long lasting

high affinity so it binds
lid formed by part of receptor protein
closes over binding pocket
temporary traps drug in place

LSD synaptic relationship

down-regulation of 5HT2A receptors

head twitch in lab animals

screen for halluncinogenic like effects in humans
5HT2A receptor-mediated behavior
elicited by all known hallucinogens that act through this mechanism

all four hallucinogens use the

5HT2A metabotropic, excitatory serotonergic mechanism

how are hallucinogens different from other drugs

do not have high abuse potential
no withdrawal symptoms
not effective reinforcers
dependence is rare

hallucinogen use disorder

tolerance develops quickly to a number of hallucinogens

what is a hallucinogenic flashback

re-experiencing hallucinations after stopping use

hallucinogen persisting perception disorder (HPPD)

mental condition triggered by memories or environment cued rememberances of a past intense experience with a drug (LSD, PCP, or marijuana)

peak experience

sense of unity or oneness, transcendence of time and space, positive mood, sense of reverence and wonder

afterglow

days-weeks
followed by long-term stage of residual effects on the patient's mood and cognitive set

phencyclidine (PCP)

anesthetic
no respiratory depression
illicit street drug (angel dust/hog)

ketamine

safer alternative to PCP
anesthetic for children and animals
prescription medication

PCP administration

powdered or pill
orally, snorted, injected, or applied to tobacco or marijuana cigarettes and smoked

subjective effects of PCP

feeling detached from body
vertigo or floating sensation
numbness
- dreamlike state

PCP affective reactions

drowsiness, apathy, loneliness, negativism/hostility, euphoria/inebriation

all PCP subjects exhibited

cognitive disorganization
difficulty maintaining concentration or focus, deficiencies in abstract thinking, halting speech
- dose-dependent

effects of PCP

symptoms of schizophrenia
- not popular

illicit ketamine use

diversion or theft of medical or veterinary material

ketamine dosage

low doses - reaction similar to PCP
doses in anesthetic rage - dissociated state "k-hole"
- spiritually uplifting or terrifying
- dissociative anesthetic

PCP and ketamine are

noncompetitive NMDA antagonists
ionotropic receptors for glutamate
blockade in cerebral cortex + hippocampus
- cognitive effects

glutamate hypothesis of schizophrenia

hypoactivity of glutametergic system - pathogenesis of the disorder
NMDA receptor antagonist model symptoms of schizophrenia
reduced NMDA receptor subunits expression in postmortem brain tissues

Corticotropin-releasing factors (CRF)

released from hypothalamus
induces anterior pituitary to release adrenocorticotropic hormone (ACTH)
releases glucocorticoids from adrenal cortex
- negative feedback and adapt to environmental challenges

HPA axis

hypothalamus -CRF-\> pituitary -ACTH-\> adrenal glads -cortisol
- negative feedback loop

CFR rodents

increased anxiety
- conflict tests, social interaction, exploration in novel open fields, elevated plus maze
stressful stimuli cause release of CFR in the amygdala
behavioral effects prevented
- pretreat with CFR antagonist

drugs for treating anxiety, OCS and PTSD

anxiolytics
sedative-hypnotic drugs - CNS depressants
- barbiturates, benzodiazepines, alcohol

anxiolytics

calm and relaxed state, drowsiness, mental clouding, incoordination
higher dose - induce sleep (hypnotics)
highest dose - induce coma and death

anxiety disorders effect what brain regions

amygdala, hippocampus, PFC

anxiety in the amygdala

emotion processing circuits
activated by negative emotional stimuli
amygdaloid processing plays central role

rodent amygdala study

electrical stimulation of amygdala produces signs of anxiety and fear
bilateral lesions \= deficits in fearful responses

anxiety vs fear

fear response - central nucleus of the amygdala (response to sudden, aversive events)
anxiety - Bed Nucleus of the Stria Terminals (BNST) initiates emotional response when stimuli less precise predictors of potential danger (sustained preparedness for unclear danger and prolonged anticipation of unpleasantness)

conditioned emotional response (CER)

makes associations between environmental stimulus and aversive stimulus
- established quickly and is long-lasting

anxiety in the hippocampus

memory consolidation
role in some anxiety disorders because reciprocal connections with the amygdala modulate emotional responses

anxiety in the PFC

exert inhibitory control over subcortical regions
- cope with situations

anxiety disorders

arise from imbalance between emotion generating centers and higher cortical control

anxiety

apprehension about future events or misfortune and our ability to deal with them