Lecture 56: Marijuana

Question 1

Where can we find cannabinoids and receptors naturally?

Answer 1

Cannabinoids are endogenously produced

Cannabinoid receptors very common in the brain

Question 2

What is the main psychoactive ingredient in marijuana?

Answer 2

Delta-9-tetrahydrocannabinol

Also THCV and Cannabidiol

Question 3

What is the major active metabolite?

Answer 3

OH-THC (11-delta-9-THC)

Question 4

Major inactive ingredient?

Answer 4

THC-COOH

Question 5

Is marijuana a gateway drug?

Answer 5

O’Brien is skeptical because kids just kind of uses whatever is available

Question 6

What are the desirable effects of marijuana?

Answer 6

1. Euphoria “high”
2. Anxiolysis “mellowing out”
3. antiemetic (used for chemo patients)
4. Analgesic
5. muscle relaxant
6. increased appetite lol
7. anti convulsant/inflammation
8. bronchodilation
9. cancer cell apoptosis?
10. reduction of intraocular tension (because of CB receptors in retina)

Question 7

What are the toxic effects?

Answer 7

1. balance/orientation
2. loss of motivation, memory, perception and even consciousness
3. Xerostomia, hypohydrosis, hypertension, tachycardia
4. Conjunctival irritation
5. Bronchopulmonary irritation
6. endocrine changes
7. Decreased Immunomodulation
8. Testicular germ cell tumors?
   
   • decrease sperm

Question 8

What is the percentage of marijuana dependence?

Answer 8

9% of those exposed

-less addictive than other drugs

Question 9

What is marijuana withdrawal syndrome?

Answer 9

Lack of physical complaints
Dysphoria
Anorexia
Irritability
Anxiety
Nonspecific somatic complaints 
(what happens to frequent users)

Question 10

When do the psychotropic effects of marijuana kick in?

Answer 10

Psychotropic effects kick in after a LAG in plasma level after inhalation

Question 11

When is the peak effect of marijuana?

Answer 11

Les than 10 minutes when inhaled

2.5 hours after ingested

Question 12

What is the distribution of marijuana in body?

Answer 12

Marijuana is lipophilic
-redistributed in fatty tissues and in chronic users could be intermittently released back into circulation over a motnh longer

Question 13

How do you detect marijuana?

Answer 13

Immunoassay in urine
Sensitive threshold = 50 ng/ml
Does not discriminate THC from metabolites
Urine levels are NOT correlated with time and amount used…unlike plasma
Single join leads to positive urine test up to 96 hours

Question 14

What are peak plasma levels of marijuana?

Answer 14

100ng/ml

Question 15

What is a potential drug for marijuana withdrawal?

Answer 15

1. Nabilone
2. Sativex
3. Buspirone
4. Dronabinol

Question 16

What are examples of synthetic marijuana (for therapy)?

Answer 16

Dronabinol (Marinol)

Nabilone (Cesamet)

Question 17

What are the significant cannabinoid receptors?

Answer 17

CB1: brain, fat cells, liver, duodenum, muscle
CB2: lymphocytes > macrophages > cytokines

Question 18

Where are CB1 receptors located?

Answer 18

Dense in the parts of the brain that control emotion
-basal ganglia
-cerebellum
-hippocampus
-NAcc
-middle prefrontal cortex 
-parietal cortex
Moderately dense in
-amygdala, spinal cord, brainstem

Question 19

What are types of ENDOGENOUS CANNABINOIDS?

Answer 19

1. Annandamaide

2. 2-arachidonoyl-glycerol (2-AG)

Question 20

What is the MOA of THC?

Answer 20

Binds to cannabinoid receptors (Gi) located on GABA interneurons
Elicits dopamine release in NAcc

Question 21

How do endocannabinoid, dopamine and opioids interact in body?

Answer 21

1. Rimonabant (CB1 antagonist) prevents morphine-induced conditioned place preference (not FDA approved because of severe mood side effects)
2. Naloxone precipitates opiate withdrawal in cannabinoid dependent rats
3. naloxone blocks cannabinoid-induced analgesia (because cannabinoid is also has a Gi receptor)

Question 22

What are the key characteristics of pharmacotherapy in relation to marijuana?

Answer 22

1. No medication has been consistently effective or approved by any national regulatory authority
2. Buspirone is the only medication to date that has shown efficacy for cannibs dependence in a controlled clinical trial
3. Laboratory and open-label trials suggest that dronabinol the COMT inhibitor entacapone, and lithium may warrant further study
4. Pre-clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes and nicotinic alpha 7 receptor antagonists such as methyllycaconitine (MLA)

Question 23

What is the association between endocannabinoids and obesity? Significance

Answer 23

Endocannabinoids and cannabinoids
-induce appetite
-reduce satiety
-stimulate lipogenesis
-increase hedonic reward value of palatable food
CB1 antagonists should have opposite effects…

Question 24

What is the therapeutic potential of CB1 antagonists?

Answer 24

Can be used to treat ADDICTION and OBESITY
1. Can block the direct reinforcing effects of THC
2. Can block the motivational effects of most drugs of abuse
Example: Rimonabant
3. Shown to prevent types of addiction of nicotine but was canceled because of severe depression side effect

Question 25

What is harmful about marijuana?

Answer 25

Marijuana delivery system (the joint) is more harmful than the substance itself