Cannabinoids & Medical Marijuana Flashcards
What is Cannabis?
- Cannabis sativa
- Hemp
- originates from Asia
- grown around the world
- hemp plant
- contains 100’s of chemical substances!!!
- many are termed “cannabinoids”
What are Cannabinoids?
- stored in trichomes
- effect cell receptors in brain/body
- effects cell communication and behaviour
What are the types of Cannabinoids?
- Phytocannabinoids
- Endocannabinoids
- Synthetic Cannabinoids
What is apart of Phytocannabinoids?
a. THC
b. CBD
c. Terpenes
What is THC?
- 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
What is CBD?
- no “high”
- may decrease effects of THC in brain
- possible therapeutic effects
What is Terpenes?
- trichromes
- distinctive smell
What are the short term health effects?
- “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
What are the long term health effects?
(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
What is the health effects with pregnancy?
- lower birth weight
- developmental effects in child: hyperactivity, memory impairment
- substances are carried in breast milk and fetal blood supply
What is apart of Endocannabinoids? What are they?
ex: 2-arachidonyl-glycerol (2-AG) and anandamide (AEA)
* endogenously produced by the body
* synthesized “on demand”
* derivatives of long chain polyunsaturated fatty acids
What is apart of Synthetic Cannabinoids? What are they?
- 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
What is the ECS?
…CB receptor agonists and the proteins, that bind, transport and metabolize these lipids
- lipid signaling system
- implicated in a number of physiological processes
What can dysfunction of the ECS can lead to?
- pain
- inflammation
- psychiatric disorders
- neurodegenerative diseases
- may contribute to other human diseases
What does the ECS consist of?
- cannabinoidreceptors
- CB1R
- CB2R - endocannabinoids
- endogenous
- e.g. 2-AG, AEA - enzymes
- synthesis
- degradation
What are the Cannabinoid receptors?
G-coupled protein receptors
* cannabinoid type 1 (CB1R)
* cannabinoid type 2 (CB2R)
Compare & contrast ECS cannabinoid receptors (CB1R & CB2R)
- 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
CB1R:
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
CB2R:
- tissues and cells of the immune system, leukocytes, spleen
- bone, liver, heart, nerve cells (astrocytes, microglia)
Other receptors:
- 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
Cannabinoid receptors ligands:
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.
Endogenous cannabinoid receptor ligands:
- synthesized “on-demand”
- neuron – action potential
- biological stimulus
- controlled system
- synthesized from phospholipid pre-cursors
- both derived from arachidonic acid
– endocannabinoids and eicosanoids
Enzymes:
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
What are the parts of the CB1R?
- THC
- Dronabinol
- Nabilone
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
Dysregulation of ECS:
- can result pathological conditions
- modulation can be harmful or beneficial
- targeting specific metabolic pathways
- antagonism or agonism of receptors
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)
What are the PD of THC?
- partial agonist of CB1 and CB2 receptors
- activity found at other targets, as well
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
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
What are the ROA for Cannabis?
- inhalation
* smoked, vaporized
* absorbed via lung - oral preparations
* edibles, capsules, sprays
* absorbed via intestine - rectally
* suppositories
* absorbed via colon - dermally
* topicals
* absorbed via skin
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
What is the absorption of VAPORIZED admin?
- bioequivalence compared to smoking not well established
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
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
What is the metabolism of Cannabis?
- occurs mainly in liver
- dependent on route of administration
What is the metabolism of THC?
oxidation - epoxidation – decarboxylation – conjugation
What is the metabolism of CBD?
- 30 different metabolites found in urine
- hydroxylated metabolites
- phase 1 metabolism - sulfation
What is the excretion of the smoked admin?
THC and CBD levels in plasma decrease rapidly after smoking
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
PK tolerance?
- changes in absorption, metabolism, excretion
- occurs with repeated use
- occurs less than PD tolerance
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
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
What is THC?
delta-9-tetrahydrocannabinol (THC)
* predominant phytocannabinoid
* well-studied
* psychoactive and physical effects
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
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
What is THC stored in?
stored in fatty adipose tissue
* slow release in bloodstream
* THC in blood detected 30 days after smoking
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
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
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
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
What is JWH 133 (synthetic cannabinoids)?
- potent CB2 receptor agonist
- 200x more selective for CB2 vs. CB1
What is K2/Spice (synthetic cannabinoids)?
- extremely potent
- mimics effects of CBD
- dangerous - can have bad SE’s
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
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
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
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
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
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
What are the pt candidates for Cannabinoids?
cannabinoids not considered 1st line or 2nd line treatments
* reserve for patients who have tried other medications
What are the contraindications of Cannabinoids?
- pregnancy/breastfeeding
- <25 years old
- history of schizophrenia
- history of substance abuse
- respiratory disease
What are the negative effects of Cannabinoids?
- substance abuse of cannabinoids
- abuse of other substances
- addiction
- cognitive function impairment
- behavioural modification (specifically in youth)
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
What is Dravet syndrome (epilepsy)?
- childhood epilepsy disorder
- drug resistant and high mortality rates
- loss-of-function gene mutation
- cognitive impairment in patients
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
What is the overview of epilepsy?
1/3rd of patients with epilepsy have seizures that are resistant to antiepileptic medications
What are the defects of the ECS in epilepsy?
- low levels of anandamide
- low CB1 mRNA
- low DAGL – (2-AG synthesis enzyme)
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
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
THC in epilepsy:
- activation of CB1 receptors
- CB1 agonists – pre-clinical research is contradictory
- reduced seizures
- had no effect
- increased convulsant activity
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
Lennox-Gavaut syndrome clinical studies:
CBD treatment
* 52% reduction in seizures
* improvement in function and quality of life
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
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
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
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
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
What are the challenges w/ Cannabis research?
- limited and small-in-size randomized control trials
* short duration, studying differing routes, forms & types of cannabinoids - 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. - cannabinoid trials are not adequately blinded due to the psychoactive effects of cannabinoids
* ~90% of patients can guess their allocation
* bias results towards benefit
