Cannabinoids & Medical Marijuana Flashcards
(78 cards)
1
Q
What is Cannabis?
A
- Cannabis sativa
- Hemp
- originates from Asia
- grown around the world
- hemp plant
- contains 100’s of chemical substances!!!
- many are termed “cannabinoids”
2
Q
What are Cannabinoids?
A
- stored in trichomes
- effect cell receptors in brain/body
- effects cell communication and behaviour
3
Q
What are the types of Cannabinoids?
A
- Phytocannabinoids
- Endocannabinoids
- Synthetic Cannabinoids
4
Q
What is apart of Phytocannabinoids?
A
a. THC
b. CBD
c. Terpenes
5
Q
What is THC?
A
- most commonly researched
- “high”
- harmful effects increase with concentration
- beneficial effects seen at lower doses
- dose - % of weight
- (1980s=3%, 2019=15%) – much higher percentage in modern cannabis
6
Q
What is CBD?
A
- no “high”
- may decrease effects of THC in brain
- possible therapeutic effects
7
Q
What is Terpenes?
A
- trichromes
- distinctive smell
8
Q
What are the short term health effects?
A
- “high” feeling
- well-being
- relaxation
- heightened senses
- confusion
- tiredness
- impaired ability to concentrate/remember
- anxiety/fear/panic
- low blood pressure
- increased heart rate
- smoke inhalation – damaged blood vessels
9
Q
What are the long term health effects?
A
(near daily use over weeks/months/years)
* increase risk of addiction
* decreased cognitive functions (memory, intelligence, decision- making)
* worsen when used in adolescence
* effects may not be reversible once stopped
* effects similar to tobacco use:
* bronchitis, lung infections, cough, mucus build-up
10
Q
What is the health effects with pregnancy?
A
- lower birth weight
- developmental effects in child: hyperactivity, memory impairment
- substances are carried in breast milk and fetal blood supply
11
Q
What is apart of Endocannabinoids? What are they?
A
ex: 2-arachidonyl-glycerol (2-AG) and anandamide (AEA)
* endogenously produced by the body
* synthesized “on demand”
* derivatives of long chain polyunsaturated fatty acids
12
Q
What is apart of Synthetic Cannabinoids? What are they?
A
- ex: CB13, JWH133, spice
- analogs of natural products, or endocannabinoids
- pharmacological probes to target specific endocannabinoid receptors
- synthetic variants are abundant
- changing chemical structure, alters:
- affinity
- potency
- selectivity
13
Q
What is the ECS?
A
…CB receptor agonists and the proteins, that bind, transport and metabolize these lipids
- lipid signaling system
- implicated in a number of physiological processes
14
Q
What can dysfunction of the ECS can lead to?
A
- pain
- inflammation
- psychiatric disorders
- neurodegenerative diseases
- may contribute to other human diseases
15
Q
What does the ECS consist of?
A
- cannabinoidreceptors
- CB1R
- CB2R - endocannabinoids
- endogenous
- e.g. 2-AG, AEA - enzymes
- synthesis
- degradation
16
Q
What are the Cannabinoid receptors?
A
G-coupled protein receptors
* cannabinoid type 1 (CB1R)
* cannabinoid type 2 (CB2R)
17
Q
Compare & contrast ECS cannabinoid receptors (CB1R & CB2R)
A
- cannabinoid receptor expression
- CB1R and CB2R have somewhat distinct tissue distribution
- both are GPCRs
- influence the release of neurotransmitters
- CB1R - is linked to the “high” and psychoactive properties of cannabis
- central nervous system activity
- CB2R – is not associated with “high”
- found in peripheral tissue
18
Q
CB1R:
A
central and peripheral nervous system
* one of the most abundant GPCRs
- cerebral cortex, hippocampus, cerebellum, etc.
also found in:
* adipocytes, leukocytes, spleen, heart, lungs, GI tract, liver, kidney, bladder, reproductive organs, bones, joints, skin
19
Q
CB2R:
A
- tissues and cells of the immune system, leukocytes, spleen
- bone, liver, heart, nerve cells (astrocytes, microglia)
20
Q
Other receptors:
A
- GPR55: g-protein coupled receptor 55
- TPRV1: transient receptor potential vanilloid 1
- PPARs: peroxisome proliferator-activated receptor
* create even more complexity for modulation of the ECS
21
Q
Cannabinoid receptors ligands:
A
a. endogenous ligands:
* endocannabinoids
* ex: 2-arachidonyl-glycerol (2-AG), and anandamide
* amides, esters, ethers
* long chain polyunsaturated fatty acids
b. exogenous ligands:
* ex: THC, CBD, synthetics, etc.
22
Q
Endogenous cannabinoid receptor ligands:
A
- synthesized “on-demand”
- neuron – action potential
- biological stimulus
- controlled system
- synthesized from phospholipid pre-cursors
- both derived from arachidonic acid
– endocannabinoids and eicosanoids
23
Q
Enzymes:
A
for synthesis and degradation
- a. synthesizing enzymes
1. phospholipase C - affinity for 2-AG
2. N-acyltransferase - affinity for anandamide
b. degradation/hydrolytic enzymes:
* terminate cannabinoid signal transduction
1. FAAH-fattyacidamidehydrolase
* post-synaptic
* affinity for anandamide
2. MAGL-monoacylglycerol
* pre-synaptic
* catabolism of 2-AG
24
Q
What are the parts of the CB1R?
A
- THC
- Dronabinol
- Nabilone
25
What is the overview of the process of the ECS?
* Endocannabinoids produced on demand on POST-SYNAPTIC terminal
* Diffuse RETROGRADE TO PRE-SYNAPTIC terminal
* Both endogenous and exogenous cannabinoids
(dronabinol, nabilone, etc.) will bind to CB1R
* Will (through series of ion channel openings) arrest of excitatory and inhibitory neurotransmitters
* Both endocannabinoids will BREAK DOWN TO ARACHIDONIC ACID
26
Dysregulation of ECS:
* can result pathological conditions
* modulation can be harmful or beneficial
- targeting specific metabolic pathways
- antagonism or agonism of receptors
27
What are the therapeutic challenges:
* selectivity in targeting disease/symptoms
* cannabis use (THC dominant strains)
- effect mood and cognition
* clinical studies: non-cancer pain (mainly neurologically)
- low does THC (smoke/vaporize) may have benefits with little psychoactive effect
-- (<3mg/dose)
28
What are the PD of THC?
* partial agonist of CB1 and CB2 receptors
* activity found at other targets, as well
29
What are the PD of CBD?
* non-competitive, allosteric modulator of CB1 receptors
* not a partial agonist to CB1 or CB2 receptors
* interacts with ion channels, other receptors and may modulate enzymes
30
What is the PK?
* limited information on interactions
- discrepancies and opposing results
* Research study discrepancies:
* dosing
* ratios (THC:CBD)
* routes of administration
* pre-treatment, co-administration (THC and CBD)
* acute vs. chronic use
* in vivo animal models
* endpoints
* most studies investigating attenuation of the psychoactive effects of THC via CBD dosing
* pre-treatment
* co-administration
* ratio alteration
* i.e. CBD:THC, 8:1 vs. 2:1
* CBD may effect THC effects
- via altering metabolism of THC in liver
31
What are the ROA for Cannabis?
1. inhalation
* smoked, vaporized
* absorbed via lung
2. oral preparations
* edibles, capsules, sprays
* absorbed via intestine
3. rectally
* suppositories
* absorbed via colon
4. dermally
* topicals
* absorbed via skin
32
What is the absorption of SMOKED admin?
* rapid onset of action
* higher concentration of cannabinoids in blood
* acute pharmacodynamic response
* THC concentration is variable
* bioavailability variable
- 2-56% absorption
* 25% of total THC content from cannabis is absorbed/delivered
33
What is the absorption of VAPORIZED admin?
* bioequivalence compared to smoking not well established
34
What is the absorption of ORAL admin?
* acute effects occur over hours
* slower onset
* lower blood levels
* longer duration of pharmacodynamic effects
* preferred by medical users
* systemic availability 4-11%, slow and unreliable
* dissolve better in fats > oils > lipid free
35
What is the absorption of TOPICAL admin?
cannabinoids are highly hydrophobic
* transport across layers of the skin are the rate-limiting step in diffusion
pre-clinical dermal patch
* CBD permeation 10x higher than THC
pre-clinical transdermal CBD gel
* dose-response seen with permeation into skin
36
What is the metabolism of Cannabis?
* occurs mainly in liver
* dependent on route of administration
37
What is the metabolism of THC?
oxidation - epoxidation – decarboxylation – conjugation
38
What is the metabolism of CBD?
* 30 different metabolites found in urine
* hydroxylated metabolites
* phase 1 metabolism - sulfation
39
What is the excretion of the smoked admin?
THC and CBD levels in plasma decrease rapidly after smoking
40
What is the excretion of the oral admin for THC & CBD?
* THC:
* 10-15% in urine, mainly biliary excretion
* phase II metabolite – glucuronidated
* CBD:
* half-life = 2 - 5days
41
PK tolerance?
* changes in absorption, metabolism, excretion
* occurs with repeated use
* occurs less than PD tolerance
42
PD tolerance?
* linked to changes in the availability of the cannabinoid
receptors
- mainly CB1 receptors
-- desensitization and downregulation in THC users
* Clinical studies:
* CB1R downregulation reversible
* 2 days saw improvement
* 28 days not significantly different than control group
43
What is THC & CBD avail for & its storage?
* available for medical and recreational use
* humidity, temperature, oxidation, light
* effect stability
* storage at 18oC over 5 years
* lost 1/3rd of THC concentration
* licensed commercial retailers in Canada
* should supply storage and expiration
44
What is THC?
delta-9-tetrahydrocannabinol (THC)
* predominant phytocannabinoid
* well-studied
* psychoactive and physical effects
45
What does THC exist as?
exists in active and inactive form in Cannabis sativa
* inactive: monocarboxylic acid
* active: decarboxylated compound
- promoted by heating (98-200oC)
-- pyrolysis (i.e. smoking)
--- promotes conversion of 100’s of cannabinoids
46
What is THC properties?
lipophilic and lipid soluble
* taken up primarily by fatty tissues
* highly perfused in organs
* brain, heart, lung, and liver
* highest THC content found in the heart
* 1000x higher that of plasma
* blood-brain barrier limits accumulation in the brain
* despite high perfusion in brain
47
What is THC stored in?
stored in fatty adipose tissue
* slow release in bloodstream
* THC in blood detected 30 days after smoking
48
What is CBD?
CBD - cannabidiol
* non-psychoactive phytocannabinoid
* interacts indirectly with endocannabinoid system
* interacts with multiple receptors:
* GPR55 - antagonist
* TPRV1 – agonist (weak)
* PPAR – agonist
* pleiotropic effects reported
* anti-inflammatory, anti-epileptic
49
What is Amandamide (endocannabinoids)?
* partial agonist of CB1 receptor, stimulates TPRV1 receptor
* 1st endocannabinoid to be discover
* plays role in:
- thought processes, control of movement, forming short-term connections between nerve cells
- immune system function, pain management
50
What is 2-AG (endocannabinoids)?
* partial agonist of CB1/CB2 receptor
* binds with higher affinity to CB2 than anandamide
* plays role in:
* appetite, immune system function and pain management
51
What is CB13 (synthetic cannabinoids)?
* dual cannabinoid receptor agonist
* peripherally restricted
* synthetically created to not cross blood-brain barrier
* lack of psychoactive effects from CB1 receptors present in brain
* peripheral effects at low doses
52
What is JWH 133 (synthetic cannabinoids)?
* potent CB2 receptor agonist
* 200x more selective for CB2 vs. CB1
53
What is K2/Spice (synthetic cannabinoids)?
- extremely potent
- mimics effects of CBD
- dangerous - can have bad SE's
54
What is Cannabidiol rx?
* US only - right now
* 98% CBD - oil-based extract
* Dose: 5 - 20 mg/kg/d
* treatment for:
* seizures
* Lennox-Gastaut or Dravet syndromes
* for patients older than 2 years of age
* give before meal
* food/fat increases absorption
55
What is Dronabinol rx (THC synthetic)?
* THC synthetic
* US only – no longer available in Canada
* treatment of:
* severe nausea from cancer chemotherapy
* AIDS related anorexia
* appetite enhancer
* Dose: 2.5–20mg of THC per day
56
What is Nabilone rx (THC synthetic)?
* synthetic THC analogue
* available in Canada
* treatment of:
* severe nausea from cancer chemotherapy
* off-label
* AIDS related anorexia
* palliative pain
* neuropathic pain
* Dose: 0.2-6 mg per day
57
What is Nabiximols (THC:CBD)?
* not available in USA
* a botanical cannabis extract containing approximately equal concentrations of THC:CBD
* plus terpenoids and flavonoids
* ora-mucosal administration
* 4 sprays: 10 mg CBD and 10.8 mg THC
* Dose: 1-16 sprays per day
* THC blood levels similar to oral administration
58
What is Nabiximols (THC:CBD) tx for?
* advanced cancer pain
* multiple sclerosis neuropathic pain or spasticity
* spasticity may require lower dose than pain
* 4-5 sprays vs. >8 sprays
59
What is the MOA of Nabiximols (THC:CBD)?
* works through CB receptors
* central nervous system and in immune cells
* contains extracts from chemically and genetically characterised Cannabis Sativa plants
60
What are the pt candidates for Cannabinoids?
cannabinoids not considered 1st line or 2nd line treatments
* reserve for patients who have tried other medications
61
What are the contraindications of Cannabinoids?
* pregnancy/breastfeeding
* <25 years old
* history of schizophrenia
* history of substance abuse
* respiratory disease
62
What are the negative effects of Cannabinoids?
* substance abuse of cannabinoids
* abuse of other substances
* addiction
* cognitive function impairment
* behavioural modification (specifically in youth)
63
What are the therapeutic targets of ECS?
* Challenging and possibly rewarding
* ECS implicated in numerous physiological and pathophysiology processes
* 1950’s
* first chemical constituents of ECS were discovered
* THC and CBD, then endocannabinoids
* ECS activated “on demand”
* cell and time-specific function during pathological state
* activation of inhibition of ECS (i.e. through CB1R)
* interference with normal CB1 function in non-target cells
* Pathological implications from altering ECS signaling
* altered expression/function of:
* CB receptors
* endocannabinoid metabolic enzymes
* CB1 is one of the most abundant and widespread GPCR in the mammalian brain
* Therapies that exploit pathological changes
* agonist/antagonists of CB receptors
* inhibitors of metabolic enzymes
64
What is Dravet syndrome (epilepsy)?
* childhood epilepsy disorder
* drug resistant and high mortality rates
* loss-of-function gene mutation
* cognitive impairment in patients
65
What is Lennox-Gastaut syndrome?
* childhood onset epilepsy
* cognitive impairment/dysfunction
* more common in males than females
* occur with no history of disorder in family – sporadic
* randomly occurs de novo during cell formation in-utero
66
What is the overview of epilepsy?
1/3rd of patients with epilepsy have seizures that are resistant to antiepileptic medications
67
What are the defects of the ECS in epilepsy?
* low levels of anandamide
* low CB1 mRNA
* low DAGL – (2-AG synthesis enzyme)
68
ECS activated by seizures:
* upregulation of CB1 receptors
* reduction of endocannabinoid metabolic degradation prevented induced seizures
* CB1 antagonists induced seizure-like discharges
* CB1 agonists prevented
69
Cannabidiol in epilepsy:
* cannabidiol shown to be effective in small pre-clinical trials
* inconsistencies between studies
* may act through GPR55
* decrease pre-synaptic glutamate
* may exert antioxidant and anti-inflammatory effects
70
THC in epilepsy:
* activation of CB1 receptors
* CB1 agonists – pre-clinical research is contradictory
* reduced seizures
* had no effect
* increased convulsant activity
71
Dravet syndrome clinical studies:
* drug-resistant seizures
* cannabidiol shown effective in clinical trials
* 2-18yo, 120 patients
* 20 mg/kg CBD
* CBD: 12.4 to 5.9 seizures per month
* placebo: 14.9 to 14.1 seizures per month
72
Lennox-Gavaut syndrome clinical studies:
CBD treatment
* 52% reduction in seizures
* improvement in function and quality of life
73
Parkinson's Disease:
* broad media interest and incredible case reports
* internet platforms showing tremendous improvement of symptoms after marijuana use
* specifically dyskinesia/tremor
* began with unusual approval in EU
* ECS and Parkinson’s:
* high level of CB receptors in basal ganglia of PD patients
* basal ganglia – controls voluntary motor movement
74
Parkinson's Disease Pre-clinical studies:
* CB1 receptor agonists
* reduce akinesia, motor impairment, tremor
* receptor-independent mechanism
* THC
* increase bradykinesia
* Cannabis may influence dopaminergic system
* synthesis and release of dopamine
* fine tuning of movement
* substantia nigra communicates with basal ganglia releasing dopemine
* in PD: neurons of substantia nigra degenerate, dopamine lowered
75
Parkinson's Disease Clinical Studies:
* numerous single cases show promise
* clinical trials for PD motor function are more rare and less promising
* randomized placebo controlled
4 randomized control trials, 3 showed no effect
* CBD, THC:CBD, nabilone as an add-on therapy
* 1 RCT showed increased motor function vs. baseline
* 1 RCT showed severity but not duration of dyskinesia improved
76
What is Parkinson's Disease MOA?
Specific mechanism of action is unknown
* might induce neuroprotective effects related to direct receptor-independent mechanisms
* activation of anti-inflammatory cascades in glial cells via CB2 receptor
* CB1 receptors may increase acetylcholine release
* may reduce cholinergic deficit in PD
77
What are the facts vs. myths?
* lots of anecdotal single case stories in media
* pre-clinical, clinical and epidemiological studies emerging
* ECS is complicated
* cannabis does have side-effects
* THC:CBD ratios
* medication comes first
78
What are the challenges w/ Cannabis research?
1. limited and small-in-size randomized control trials
* short duration, studying differing routes, forms & types of cannabinoids
2. difficult to assess benefits
* trials with longer duration tend to show less benefit
* implying that if an effect exists, it may wear off over time.
3. cannabinoid trials are not adequately blinded due to the psychoactive effects of cannabinoids
* ~90% of patients can guess their allocation
* bias results towards benefit
