Final: Cannabinoids Flashcards
Marijuana
Various parts of female/male cannabis plants
Sensimilla
potent form from flower of female palnts kept seedless by preventing pollination to promote a high THC content
Hashish
Sticky, thick, dark colored resin form of flower of female plants
Transdermal
lipid soluble
very lipophilic
How do you take marijuana?
Oral (ingestion) and inhalation
Also transdermal
What’s interesting about taking weed orally?
Generally, most things don’t survive first pass, but THC does.
Hepatic portal system, 1st pass.
**Primary metabolite is more psychoactive than precursor.
(11-OH-THC)
THC binds __ and __ receptors
CB1- brain and CNS
CB2- spleen, immune cells, periphery, tonsillar cells
CBN
CB1 and CB2, psychoactive,
Hard time cross BBB, CB2 selective
CBD
bind CB1 and CB2, doesn’t have high affinity
Antagonist low intrinsic activity
Also potentiates opioid receptors, agonist at serotonin
Anandamide (AEA)
partial agonist at only CB1
Endocannabinoid
2-AG
2-arachidonoylglycerol
Full agonist at CB1 and CB2
Endocannabinoid
Degradation:
Anandamide and 2-AG cleaved by enzymes….
1) FAAH (AEA)
2) MAGL (2-AG)
this makes arachidonic acid
No vesicle release
Although Ca2+ induces release, it’s not vesicles? Why and how?
Too lipophilic for vesicles
Since cleaved from phospholipids, cleaving is Ca2+ Dependent (Ca2+ dependent enzymes)
Cannabinoid receptors:
1) inhibit cAMP (adenylyl cyclase)
2) Open K+ Channels (IPSP, hyperpolarization on dendrites/cell body, postsynaptic)
3) Close voltage gated Ca2+ channels (presynaptic inhibition)
4) influence gene expression, MAP kinase system
Acute inhibitory functions
Endocannabinoids are ____ transmitters
retrograde.
release postsynaptic synapse, travel back to presynaptic synapse.
Why would we need retrograde endocannabinoids?
Modulate signaling that gets out of hand.
Inhibit inhibition, so they are excitatory.
Rely on endocannbinoids in descending pain pathways where pain signal happens.
Endocannabinoid functions:
- Modulate pain, anxiety, nausea, immune responses
- Feeding
- Learning and Memory
Rimonabant
selective CB1 antagonist
Desired effects of cannabinoids
Depressant-like effects
Calm, relaxed, dream like state
Mild feeling of euphoria, exhilaration
Mild psychedelic effects
slowed sense of time, depersonalization, altered perceptions unusual imagery
Adverse effects of cannabinoids
Weak somatic side effects, increase heart rate, bp, dry mouth, dizzy
Impaired motor functioning
Impair cognitive functioning
Stimulate appetite
How does cannabinoid dependence and pharmacodynamic tolerance work?
1st wave- G protein activated
2nd wave- beta arrestin activated
3rd wave- G protein and beta arrestin
Low dose: increase receptor effect
high Does: no effect (pharmacodynamic tolerance)
Why not too bad physical withdrawal?
hint: excretion
THC excreted in solid waste, but also fat deposits, so slowly it comes out after you stop.
What INDUCES withdrawal in chronic users?
Withdrawal symptoms
Rimonabant, selective CB1 antagonist
induces withdrawal in chronic users
Symptoms: mild irritability, anxiety, disturbed sleep, decreased appetite
Long term psychosis health outcome
3x more likely reality disturbances
Control for potency, areas with more potent strains have higher rates of psychosis
Long term cognition
8 IQ points- is drug doing that?
memory deficits and decision making/planning deficits.
Marijuana and Reward
weed first time high dose, psychosis short time
However, look at PET scans for change in D2/D3 receptors: not conclusive
Where do retrograde endocannabinoids act in mesolimbic pathway?
presynaptic terminals of GABA that synapses to dopamine in VTA.
Inhibit inhibition, but not specific, lots of inhibition everywhere.
Dopamine release –> release endocannabinoids, which go to gaba and instead of quieting, move backwards to remove inhibitions
Mesolimbic: inhibit inhibition at VTA
Cannabinoid Medication
Anti-emetic, Analgesic, Appetite stimulant, Treatment of glaucoma, Treatment of muscle spasms, Anti-inflammatory, Immunosuppressant
Medical weed: Nabiximols
1/2 THC
1/2 CBD
Spray
Treats: MS/MN death
(imbalance in inhibitory/excitatory motor input: SPASTICITY)
Stimulates CB1 receptors to act like articifical feedback mechanisms on excitatory glutamatergic neurons
Non-THC therapeutic targets in endocannabinoid system:
Pain insensitivity, mutation in enzyme that degrades AEA (FAAH). More circulated AEA. Makes insensitive to pain.
Why don’t 2-AG also rise with mutation? It’s different. Not actually cannabinoids, alter enzymes.
Medical weed: Lenabasum
analog of metabolite of non-psychoactive THC
Specific for CB2 receptors
unable to cross BBB
binds on immune cells, prevents biosynthesis of signals that prolong immune responses and stimulate scarring pathways.
Accelerate speed bacteria is cleared from infection
Medical weed: Rimonabant
Suppress appetite (Anti-obesity) CB1 antagonist
Lose weight, but psychiatric effects, depression, anxiety, respiratory infection.
Safer alternative: CB1 antagonist that doesn’t cross BBB.
however, CB1 in periphery affect metabolism. in liver, activation elevates blood glucose, insulin, fatty acid metabolism.
Weed is very
Lipophilic
Pathway inhaled THC
circulation, sharp peak in [plasma THC]
Declines an goes to tissue
What is the primary psychoactive ingredient in THC?
Delta 9 THC
more potent cannabis has
higher THC concentration
CB1 and CB2 receptors: what do they do?
metabotropic
linked to number of acutely inhibitory signaling cascades
Is the end result of cannabinoids inhibition or excitation?
They are always inhibitory BUT could inhibit or inhibitory or excitatory cells. So end result not always inhibition
How do endocannabinoids work as PRIMARILY RETROGRADE MESSENGERS?
They travel backwards across the synapse to affect the presynaptic cell. When they bind to presynaptic CB1, they block voltage gating Ca2+ channels, and vesicles release transmitter from presynaptic terminal.
Behaviors related to endocannabinoids
pain, anxiety, nausea, learning, memory, feeding
THC binds to CB1 receptors and causes…
Mild depressant/psychedelic
in striatum/BG/cerebellum: impairs psychomotor function
temporarily undermines memory consolidation and executive skills
increase heart rate and bp
Psychosis if high dose new user
Pharmacodynamic tolerance
cells downregulate CB1 receptors and overstimulated receptors desensitize
Behavioral side effect tolerance
infrequent user more vulnerable, but it’s dose dependent, even high users can’t escape at high doses
Overall, tolerance and dependence on weed is
mild
Physical consequences of weed
more harmful than cigarette, burn joint faster, breathing deeper, hold smoke in lungs longer
Why synthetic cannabis associated with more serious risks than natural cannabis?
Because synthetic not only fully agonist, they have high affinity for CB1 receptors
Some people call THC full agonist, some partial, does have weaker affinity than synthetics
Why are endocannbinoids and what is their importance in normal functioning?
involved in many things, pain, appetite reward
