Cannabis (Midterm II)

Question 1

cannabis

Answer 1

• a genus of flowering plant with three subgenuses (sativa, indica, and ruderalis) that have all been bred for psychoactive effects
• they contain many bioactive compounds, but the most studied are THC and CBD
• THC is the primary psychoactive compound in cannabis

Question 2

cannabinoids

Answer 2

• a class of chemicals that act at the cannabinoid receptors
• these enclude endogenous (endo) cannabinoids, those naturally occurring in the cannabis plant (phytocannabinoids), as well as synthetics

Question 3

terpenes/terpenoids

Answer 3

• non-cannabinoid constituents of the cannabis plant which give the characteristic skunky smell
• don’t bind to cannabinoid receptors but may contribute to overall experience
• some have been found to have anti-inflammatory, anti-bacterial, and anti anxiety effects in vitro/vivo, but no clinical trial support

Question 4

cannabis: absorption

Answer 4

• smoking provides rapid and efficient deliver from lungs to the brain, ditto vaping; it’s quick and easy to titrate dosage
• bioavailability of smoked THC is 25%, reaching peak plasma conc in 6-10 minutes
• when ingest, bioavailability is ~6%, and plasma conc takes 2-6 hrs to peak; titration is much more difficult and people can easily get into toxic side effects

Question 5

THC distribution

Answer 5

• THC is highly lipophilic and is rapidly taken up by tissues with high blood flow (including heart, lungs, brain and liver)
• tissues with less blood flow accumulate THC more slower, and release in over a longer period of time (ex adipose)
• in chronic, frequent smokers, THC stored in fat can be released into the blood for days

Question 6

THC: metabolism

Answer 6

• occurs mostly in the liver by CYP2C9

- this first produces 11-OH-THC, an active metabolite, then THC-COOH, an inactive metabolite

Question 7

THC elimination

Answer 7

• within 5 days, 80-90% of a dose is excreted (primarily as metabolites, with 65% leaving in the feces and 25% in the urine)
• THC can be detected in urine for 2-5 days following low dose use, but this can extend to weeks in chronic daily cannabis smokers (bc THC is highly lipophilic and accumulates in adipose tissue from which it is slowly released over time)

Question 8

cannabinoid receptors

Answer 8

• both CB1/2 are Gi coupled receptors that lead to a decrease in cAMP accumulation, which inhibits influx of Ca in firing neuron, inhibiting NT release and synaptic transmission
• CB1s are some of the most abundant GPCRs, found in the brain, peripheral organs (heart, liver, fat, stomach, testes) and peripheral nerves
• CB2 are found mostly on immune cells

Question 9

CBD/THC interaction at CB1

Answer 9

• THC is a partial agonist
• the mechanism of CBD is poorly understood, but some evidence suggests it may be a negative allosteric modulator whose binding will blunt the psychotropic effects of THC

Question 10

effects of THC

Answer 10

general: euphoria, relaxation, disinhibition of mood, changes in perception, vasodilation, increased pulse
potential therapeutic: attenuation of nausea, increased appetite, decreased intraocular pressure, chronic pain relief
unwanted: memory impairment, dysphoria, visual hallucinations (esp at rly high doses), depersonalization, psychotic episodes

Question 11

therapeutic potential for CBD

Answer 11

-preclinical research suggests management of inflammation, anxiety, emesis (vomiting), nausea, inflammatory pain, and epilepsy may all be aided, but clinical data lacking for these claims

Question 12

adverse effects of cannabis

Answer 12

-acute: panic attacks, severe anxiety, psychosis, paranoia, convulsions, hyperemesis (rare, usually as’d with high doses of THC)
-prenatal: effects on fetal growth, and may lead to neuroanatomical and behavioural changes in offspring
-lung cancer
-impairment of perception, psychomotor performance, cognitive and affective functions, decreased reaction time
NOTE: no evidence of death exclusively attributed to cannabis OD, likely bc CB1 receptors are sparse in the brainstem

Question 13

cannabis and psychosis

Answer 13

• correlative data suggests schizophrenics are more likely to use cannabis, and early cannabis use dose-dependently predicts the development of schizophrenia later on, but these studies don’t take causation into account
• the most significant link btw cannabis use and psychosis is in young uses who have the Val/Val polymorphism (a single AA change at both alleles of the COMT gene, which is important for metabolizing durg NTs in the brain)

Question 14

cannabis and tolerance

Answer 14

-chronic activation of CB1 receptors leads to uncoupling from downstream signal transduction events or receptor downregulation (internalization or degradation)

Question 15

cannabis and dependence

Answer 15

-withdrawal is generally mild and short lived; symptoms include restlessness, irritability, mild agitation, insomnia, nausea and cramping

Question 16

synthetic cannabinoids

Answer 16

-manufactured compounds whose properties imitate those of the active constituents of cannabis
give increased target specificity (useful for examining desired effects at a given receptor), decreased off target effects, easier dosing (deliver a consistent concentration of known chemicals) and overall lead to better controlled studies

Question 17

medical uses for synthetic cannabinoids

Answer 17

well confirmed clinical effects: refractory vomiting/nausea, anorexia appetite loss, HIV/AIDS/cancer cachexia (chronic wasting disease)
less well confirmed clinical effects: spasticity due to spinal cord injury, MS, neurogenic pain, neuropathy, allodynia, mvmt disorders (tourette’s, dystonia, dyskinesia), bronchodilation, glaucoma
largely unexplored but possible clinical effects: epilepsy, hiccups, BPD, alzheimers, alcohol dependent

Question 18

nabilone

Answer 18

• a synthetic analogue of THC, developed for treatment of chronic pain
• taken orally, and with less psychotropic effects than cannabis

Question 19

dronabinol

Answer 19

• trans isomer of THC, a synthetic cannabinoid approved for nausea and vomiting in patients who undergo chemotherapy, and anorexia in AIDS wasting syndrome
• taken orally and has less psychotropic effects than cannabis

Question 20

nabiximols (sativex)

Answer 20

• a botanical drug, cannabis extract (considered a synthetic cannabinoid)
• a 1:1 mixture of THC and cannabinol in the form of a sublingual spray
• the first product licensed in canada for relief of pain in adult patients suffering from MS or cancer
• less psychotropic effects than smoked cannabinoids

Question 21

rimonabant

Answer 21

• an inverse agonist at the CB1 receptor
• remember that THC stimulates appetite, so rimonabant suppresses it
• originally approved for treatment of obesity, but later withdraw due to serious side effects (depression, suicidal ideation)

Question 22

endocannabinoids

Answer 22

• mediate mood, feeding, and motor structure
• come in two flavours: anadamine (AEA) and 2-arachinoyl glycerol (2-AG)
• both are synthesized from membrane phospholipids and can therefore not be stores in vesicles (this means they are synthesized on demand when and where needed)
• they are retrograde NTs, acting on the presyn terminal to brake and quite the system once signals have been initiated

Question 23

endocannabinoid metabolism

Answer 23

AEA and 2AG are rapidly cleared from the synapse and inactivated by fatty-acid amide hydrolase (FAAH) or monoacylclygerol lipase (MAGL); suppressing the activity of these enzymes will prolong the activity, which may promote pain relief and increase appetite in a more subtle way

Question 24

medical uses of FAAH/MAGL inhibitors

Answer 24

• inhibition of these enzymes which degrade endocannabinoids would enhance CB1 activation where AEA and 2AG lvls are highest (not throughout the brain, because these endocannabs are synthesized on demand where needed)
• inhibitors don’t produce typical THC effects (psychoactivity, sedation, catalepsy or hypothermia) but do have analgesic effects and may therefore be useful for the treatment of chronic pain
• recent clinical trials have been halted though, due to several severe adverse events including death