Final: Cannabinoids Flashcards by jnauman@tulane.edu Nauman

Marijuana

Various parts of female/male cannabis plants

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Sensimilla

potent form from flower of female palnts kept seedless by preventing pollination to promote a high THC content

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Hashish

Sticky, thick, dark colored resin form of flower of female plants

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Transdermal

lipid soluble

very lipophilic

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How do you take marijuana?

Oral (ingestion) and inhalation

Also transdermal

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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)

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THC binds __ and __ receptors

CB1- brain and CNS

CB2- spleen, immune cells, periphery, tonsillar cells

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CBN

CB1 and CB2, psychoactive,

Hard time cross BBB, CB2 selective

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CBD

bind CB1 and CB2, doesn’t have high affinity

Antagonist low intrinsic activity

Also potentiates opioid receptors, agonist at serotonin

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Anandamide (AEA)

partial agonist at only CB1

Endocannabinoid

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2-AG

2-arachidonoylglycerol

Full agonist at CB1 and CB2

Endocannabinoid

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Degradation:

Anandamide and 2-AG cleaved by enzymes….

1) FAAH (AEA)
2) MAGL (2-AG)

this makes arachidonic acid

No vesicle release

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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)

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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

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Endocannabinoids are ____ transmitters

retrograde.

release postsynaptic synapse, travel back to presynaptic synapse.

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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.

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Endocannabinoid functions:

Modulate pain, anxiety, nausea, immune responses
Feeding
Learning and Memory

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Rimonabant

selective CB1 antagonist

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Desired effects of cannabinoids

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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

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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?

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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

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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

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Rimonabant, selective CB1 antagonist

induces withdrawal in chronic users

Symptoms: mild irritability, anxiety, disturbed sleep, decreased appetite

Long term psychosis health outcome

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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

Final: Cannabinoids Flashcards

(47 cards)