Cannabinoids Flashcards
endocannabinoids
anandamide (AEA) and 2-arachidonylglycerol (2-AG)
- released into synaptic cleft and bind CB1 and CB2 receptors on the PRESYNAPTIC axon terminal
Anandamide
AEA
- synthesized from NAPE by NAPE phospholipase D in the postsynaptic neuron
- metabolized by fatty acid amide hydrolase (FAAH) to ethanolamine and arachidonic acid in POSTsynaptic neuron
2-arachidonylglycerol
2-AG
- also synthesized in post-synaptic neuron by diacylglycerol lipase (DAGL)
- metabolized by monoacylglycerol lipase (MAGL) in the presynaptic neuron
CB1R
- where
- what signalling cascades are linked
- main cannabinoid receptor
- found on many different presynaptic neurons (not just GABAergic) and also on mitochondrial membrane
- Biased signalling occurs - different conformation of the receptor and thus diff signalling depending on ligand:
- beta arrestin 1 pathway leading to late activation of ERK1/2 (kinase)
- g-protein pathway (Gi) which leads to reduced AC activity and less cAMP, and reduced calcium influx (VGCC) and activates GIRK (inwardly rectifying potassium) channels
Endocannabinoids vs phytocannabinoids
endocannabinoids are endogenous cannabinoids, AEA and 2AG
- involved in appetite, pain processing, stress & anxiety, and learning & memory
phytocannabinoids include 9deltaTHC and cannabidiol (CBD)
THC
Difference between THC and CBD
THC:
- effects include: euphoria, appetite stimulant, analgesic, anti-emetic, psychosis, memory effects, hallucination
- agonist of CB1 and CB2 receptor
CBD:
- does not cause a ‘high’, anti-epilepsy
- unclear how it works
How does THC work?
Binds to CB1 receptors on glutamatergic and GABAergic neurons disrupting normal endocannabinoid retrograde signalling from dopaminergic neurons.
- endocannabinoids fine-tune the activity of the mesolimbic dopamine projections through modulating both excit and inhib signalling (the endocans. are made in the post-synaptic neuron and diffuse back into both glutamatergic and GABAergic neurons nearby that are involved in VTA signalling)
- THC fucks this up ^
ENDOCANNABINOIDS regulate the balance of glutamate and GABA signalling - which kind of explains how it can have varying effects - are you inhibiting an inhibitor or an excitor?
tolerance and cannabis
- decreased response to same dose with repeated exposure
- more drug needed to achieve same effect
- caused by compensatory mechanisms that oppose the effects of the drug
- CB1Rs normally inhibits NT release but with high-affinity ligand present the CB1Rs are downregulated and internalized so there is less inhibition of Nt release (tolerance to drug but also to endocannabinoids)
How do we make endocannabinoids
- stress
- exercise
- hunger
- pain
- time of day dependent
Biphasic effects of cannabinoids
variable, individual genetic effects and also dosage dependent, or maybe the ratio of THC to CBD matters
- remember you’re inhibiting both GABAergic and glutaminergic neurons. Balance.
endocannabinoids are involved in:
- cognitive function, attention, motivation
- appetite
- learning and memory
- vomit reflex
- pain control
- emotion and fear
THC is involved in:
- cognitive impairment
- appetite stimulation
- memory impairment
- can cause nausea or help with it
- can cause you to be hyper sensitive or help with pain
cannabis use disorder and withdrawal symptoms
you CAN develop dependence leading to withdrawal symptoms in some people when they cease usage.
withdrawal symptoms: irritability, mood and sleep difficulties, decreased appetite, cravings, restlessness
why AREN’T endocannabinoids and THC equivalent
Endocannabinoids act at the right time and right place, are precise and tightly controlled, and responsive
THC is imprecise and has multiple effects at once and affects all the systems
Why are the effects of THC hard to predict?
Sometimes you get varying effects because the THC can mimic natural cannabinoid signals but can have the opposite effect with heavy use or a high dose (starts to oppose endocannabinoid system)
- dose-dependent and dependent on endocannabinoid levels
cannabis use is associated with reduced ____ in the ___
- dopamine
- striatum
important requirements for a new medicine
- therapeutic target (can THC help with pain)
- selectivity
- suitable pharmacokinetics
- metabolic stability
- good bioavailability
- reliability
clinical efficacy - does it work?? and is it safe - absence of serious unwanted effects
Which kinds of studies provide the strongest evidence? the weakest?
- meta-analyses, systematic reviews
- in vitro studies
Cannabis as a medicine (history)
Exploited as medicine for at least 5000 years
- symptoms of dysentery and cholera
- swellings, bruises, pain (topical app)
- toothache, headache, pain from minor surgery
- arthritis, rheumatic, labour and menstrual pain
- nausea & vomiting, lack of appetite
- insomnia and fever
- spasms, cramps, and convulsions
Why is it thought that THC could help with pain?
- Endocannabinoid levels are increased during pain
- CB receptors are found in the pain pathway / in brain regions important in pain processing
- when CB receptors are activated they reduce pain (preclinical research studies in rodents show activation of CB1 leads to decreases in feeling of pain)
Clinical evidence for effectiveness of cannabis?
(conclusive, moderate, and limited)
- conclusive / substantial evidence that cannabis or cannabinoids are effective for the treatment of pain in adults: chemo-induced nausea, vomiting, spasticity associated with MS
- moderate evidence for treating SECONDARY sleep disturbances
- limited evidence for supporting improvement in appetite, tourettes, anxiety, PTSD, cancer, IBS, and ND disorders
BUT WE NEED MORE RESEARCH
CBD might have an effect in..
epilepsy
- but it might also just be decreasing liver metabolism of the drug treating the epilepsy
cannabis effects
- dizziness, drowsiness, lightheaded, fatigue
- impaired memory and attention, concentration, ability to make decisions
- disorientation, feeling confused, ‘drunk’, feeling of unreality, slow sensation of time
- suspiciousness, nervousness, anxiety, panic, paranoia
- impairment of motor skills, altered bodily perceptions
pharmacological properties of inhaled cannabis
- THC peaks within an hour
- 11-OH-THC (psychoactive metabolite) never reaches a very high plasma conc, about 20% of THC levels)
pharmacological properties of oral cannabis
THC and 11-OH-THC levels are comparable
Unwanted side-effects of THC in cannabis
- psychoactive effects
- signs of SZ in some vulnerable individuals
- falls in blood pressure (postural hypotension)
- increased HR
- risk of cancer when smoked (tars from burnt material)
- dependence and withdrawal
- impairment (driving and certain jobs)
The good, the bad, and the challenging about THC as a med
the good: pain relief in MS, anti-nausea, epilepsy treatment
the bad (side FX): impairs short-term memory, impairs attention and other cognitive functions, impairs driving, hyperemesis
the challenging: risk of psychosis in vulnerable individuals, can lead to cannabis use disorder, maternal use pregnancy and nursing
Cannabis medications currently in use
- Epidiolex (CBD oral solution) - used for treating seizures
- Marinol (oral capsule, synthetic THC) - used for treating anorexia associated with weight-loss in AIDS patients and N/V in chemo patients
- cesamet (nabilone) - synthetic THC-adjacent, used for N/V in chem patients
- Sativex (THC and CBD oromucosal spray) - used for symptom improvement in adults with treatment-refractory MS spasticity
Health Canada acts relevant to cannabis
non medical cannabis act (Cannabis Act), medical cannabis (Cannabis Act), health products with cannabis (Cannabis Act and FDA)
