17 Cannabis

Question 1

What is cannabis?

Answer 1

Genus of flowering plant;

• contains many bioactive compounds but most studied are tetrahydrocannabinol (THC) and cannabidiol (CBD)
• THC is primary psychoactive compound

Question 2

What are cannabinoids?

Answer 2

Class of chemical compounds that act at the cannabinoid receptors

Question 3

What constituent of cannabis gives it its characteristic smell?

Answer 3

Terpenoids

Question 4

In vitro and in vivo studies have found that some terpenoids have _________, _________ and _________ effects, but no clinical trials have been conducted to support this

Answer 4

In vitro and in vivo studies have found that some terpenoids have anti-inflammatory, antibacterial and anti-anxiety effects, but no clinical trials have been conducted to support this

Question 5

Why is it difficult to create a clinically appropriate form of cannabis?

Answer 5

Cannabis contains hundreds of phytocannabinoids at varying concentrations between different plants and the effect of cannabis is possibly due to surround effect, or synergy between the compounds

Question 6

Pharmacokinetics of THC:

ADME

• Bioavailability of smoked THC vs ingested
• Time to peak plasma concentration?

Answer 6

Absorption (bioavailability):

• smoking provides rapid and efficient delivery from lungs to the brain
  
  • bioavailability of smoked THC is 25%, reaching peak plasma concentration in 6-10 minutes
• Ingested:
  
  • bioavailability ~6% (because of 1st pass metabolism)
  • Time to peak plasma concentration is 2-6 hours

Question 7

Pharmacokinetics of THC:

ADME

How is THC distributed?

Answer 7

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

Question 8

THC metabolism occurs mostly in the ______ by the enzyme __________

Answer 8

THC metabolism occurs mostly in the liver by the enzyme cytochrome P450 2C9 producing the metabolites:

• 11-OH-THC
• THC-COOH

Question 9

THC metabolism occurs mostly in the liver by the enzyme cytochrome P450 2C9 producing what 2 metabolites?

Answer 9

THC metabolism occurs mostly in the liver by the enzyme cytochrome P450 2C9 producing the metabolites:

1. 11-OH-THC
2. THC-COOH

Question 10

How long does it take for THC to be excreted and in what form?

Answer 10

Within 5 days 80-90% of a THC dose is excreted, primarily as metabolites

• 65% in feces
• 25% in urine

Can detect THC in urine 2-5days for low dose, and longer (weeks) for chronic users (because it accumulates in fat tissue)

Question 11

What kind of receptors are cannabinoid receptors?

What are the 2 “flavours”?

Answer 11

Inhibitory G-protein coupled receptors (Gi coupled)

1. CB1
2. CB2

Question 12

What effect does an agonist binding to a CB receptor have?

Answer 12

CB receptors leads to decrease in cAMP (cyclic adenosine monophosphate) accumulation which inhibits the influx of Ca2+ in the firing neuron and inhibits NT release

(↓cAMP → ↓Ca2+ → ↓NT release

Question 13

What effect do CB receptors have on synaptic transmission and NT release?

Answer 13

decrease synaptic transmission

inhibit NT release

Question 14

THC is a _________ at CB1

(partial agonist, full agonist, antagonist)

Answer 14

THC is a partial agonist at CB1

(partial agonist, full agonist, antagonist)

Question 15

Cannabidiol (CBD) is poorly understood but some evidence suggests that it acts as a ______ at CB1

Answer 15

Cannabidiol (CBD) is poorly understood but some evidence suggests that it acts as a Negative Allosteric Modulator at CB1 (binds outside the binding pocket to block receptor activation)

Question 16

How do CBD and THC compete at the CB1 receptor?

Answer 16

CBD can blunt psychotropic effects of THC

Question 17

Which of the two CB receptors are more abundant in the brain?

Answer 17

• CB1 receptors are among the most abundant GPCRs
  
  • Found in brain, peripheral organs (heart, liver, fat, stomach testes) and peripheral nerves (ie found almost everywhere)
• CB2 mostly on immune cells
  
  • glial cells in the brain

Question 18

What does preclinical research suggest about CBD therapeutic potential?

Answer 18

CBD has potential for management of inflammation, anxiety, emesis, nausea, inflammatory pain, and epilepsy

• may influence effects of THC
• No clinical data for these claims

Question 19

What are 6 general effects of THC?

Answer 19

1. euphoria
2. relaxation
3. disinhibition
4. changes in perception
5. vasodilation
6. increase pulse

Question 20

What are four potential therapeutic effects of THC?

Answer 20

1. attenuation of nausea
2. increased appetite
3. decreased intraocular pressure
4. chronic pain relief

Question 21

What are five unwanted effects of THC?

Answer 21

1. memory impairment
2. dysphoric state
3. visual hallucinations
4. depersonalization
5. psychotic episodes

Question 22

What are four adverse effects of cannabis use?

Answer 22

1. Acute effects (rare and usually associated with high doses of THC)
   
   • Panic attacks
   • severe anxiety
   • psychosis
   • paranoia
   • convulsions
   • hyperemesis
2. Prenatal effects
   
   • may lead to neuroanatomical and behavioural changes in offspring
   • fetal growth, particularly neurodevelopment, but dose-response relationship not identified
3. Lung cancer : particularly through smoked cannabis
4. Driving:
   
   • increase risk of MVA
   • Impairs perception, psychomotor performance, cognitive functions and affective functions
   • Decreased rxn time

Question 23

What is the probable reason why there have been no documented evidence of death exclusively linked to cannabis overdose?

Answer 23

Because of sparsity of CB1 receptors in the brain stem region that controls respiratory and cardiovascular systems

Question 24

How is cannabis linked to schizophrenia?

Answer 24

Strictly through correlation

• correlative data suggests schizophrenics are more likely to use cannabis and early cannabis use dose-dependently predicts the development of schizophrenia later on
• these studies do not indicate causation
• Majority of cannabis users do not develop schizophrenia
  
  • however, cannabis can elicit acute psychosis and can worsen course of pre-existing schizophrenia
    
    • may be trigger in the development of schizophrenia in at-risk populations (ie those with genetic predisposition)

Question 25

How is tolerance achieved from cannabis use?

Answer 25

Chronic activation of CB1 receptor uncouples from intracellular downstream signal transduction events or **receptor downregulation** (internalization or degradation of receptor)

Question 26

Define psychological dependence?

Answer 26

compulsive drug-seeking behaviour in which the individual uses the drug receptively for personal satisfaction, often in the face of known risks to health

Question 27

What is physiological dependence?

Answer 27

revealed when withdrawal of the drug produces symptoms and signs that are frequently opposite of those sought by the user

Question 28

What are the symptoms associated with cannabis withdrawal?

Answer 28

Cannabis withdrawal is relatively mild and short-lived Symptoms: * restlessness * irritability * mild agitation * insomnia * nausea * cramping May be worse in chronic, long-term users and may contribute to continued drug use

Question 29

How is substance use disorder (addiction) defined and how is it diagnosed? How many cannabis users develop a substance use disorder?

Answer 29

Defined as the inability to control the use of legal or illegal substances despite negative consequences * diagnosed by 11 diagnostic criteria * severity is determined by the number of criteria the person meets (mild 2/11; 4/11 moderate; 6+/11 severe) * Approximately 9% of those who use cannabis develop a substance use disorder (taken prior to legalization)

Question 30

What are synthetic cannabinoids and why bother developing them?

Answer 30

Synthetic cannabinoids: a manufactured compound whose properties imitate those of the active constituents of cannabis Why? * increased specificity * decreased off-target effects * easier dosing * better controlled studies

Question 31

What are three well-confirmed clinical uses of cannabinoids?

Answer 31

1. Refractory nausea/vomiting 2. anorexia appetite loss 3. HIV/AIDS/cancer cachexia

Question 32

What is nabilone?

Answer 32

* Synthetic analog of THC * partial agonist at CB1 receptor * taken orally (less psychotropic effects than cannabis)

Question 33

What is dronabinol?

Answer 33

* (-) trans isomer of delta9-THC * Approved for nausea and vomiting in patients who undergo chemotherapy and anorexia in AIDS wasting syndrome * Partial agonist at the CB1 receptor * Taken orally = less psychotropic effects

Question 34

What is nabiximols (sativex)? When was it first licensed in Canada and for what use?

Answer 34

Botanical drug (cannabis extract) * 1:1 mixture of THC and cannabinol, sublingual spray * First licenced in Canada for relief of pain in those with multiple sclerosis or cancer * Less psychotropic effects than smoked cannabinoids

Question 35

What is Rimonabant? What was it approved to treat and what are its adverse effects?

Answer 35

Rimonabant is an inverse agonist at the BC1 receptor * originally approved for the treatment of obesity but withdrawn due to serious adverse effects (depression and suicide)

Question 36

What are endocannabinoids? Two types?

Answer 36

Endogenous cannabinoids that mediate mood, feeding and motor function * Two types * Anandamide (AEA) * 2-arachidonoyl glycerol (2-AG)

Question 37

Where are AEA and 2-AG made?

Answer 37

AEA and 2-AG (the endocannabinoids) are made from the phospholipid bilayer of the cell membrane

Question 38

AEA and 2-AG are ___________ (act on receptors on pre-synaptic membrane)

Answer 38

AEA and 2-AG are _retrograde NT's_ (act on receptors on pre-synaptic membrane)

Question 39

In contrast to most NT's, AEA and 2AG are not stored in vesicles, but rather _________ when and where they are needed

Answer 39

In contrast to most NT's, AEA and 2AG are not stored in vesicles, but rather _synthesized on demand_ when and where they are needed

Question 40

Like THC, endocannabinoids ______ neuronal release of other transmitters

Answer 40

Like THC, endocannabinoids _decrease_ neuronal release of other transmitters * via hyperpolarizing membrane

Question 41

What stimulates the synthesis of 2AG or AEA?

Answer 41

Synthesis of 2AG or AEA (endocannabinoids) is stimulated by *increase in intracellular [Ca2+] when the postsynaptic neuron becomes depolarized by the action of a NT* * therefore, produced only in regions of brane that are activated

Question 42

AEA and 2AG are rapidly cleared from the synapse and inactived by ____________ or \_\_\_\_\_\_\_\_\_\_\_.

Answer 42

AEA and 2AG are rapidly cleared from the synapse and inactivated by _fatty-acid amide hydrolase (FAAH)_ or _monoacylglycerol lipase (MAGL)_.

Question 43

Suppression of fatty-acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) would have what effect?

Answer 43

These enzymes (FAAH and MAGL) inactivate and clear AEA and 2AG so suppression of these enzymes prolongs the activity of endocannabinoids

Question 44

Inhibition of AEA or 2AG metabolism would have what effect on CB1?

Answer 44

Because AEA and 2AG are synthesized and released on demand at the site of action, inhibition of their metabolism would enhance CB1 activation where AEA and 2AG levels are highest - FAAH/MAGL inhibitors

Question 45

What are the effects of FAAH/MAGL inhibitors in comparison to effects of THC? What halted clinical trials?

Answer 45

FAAH/MAGL inhibitors do not produce typical psychoactive effects of thc, sedation, catalepsy or hypothermia BUT do have analgesic effects * several compounds under development for the treatment of chronic pain * Clinical trials halted because of several severe adverse events from a FAAH inhibitor * brain damage, one death