Drugs of abuse 1 - General/Cannabis

Question 1

Generally speaking, how do the drugs of abuse cause the feeling of euphoria?

Answer 1

The hijack the mesolimbic dopaminergic pathway – the central reward pathway

Question 2

Describe the central reward pathway.

Answer 2

The dopaminergic neurones project from the ventral tegmental area to the nucleus accumbens
Dopamine release into the nucleus accumbens will stimulate the feeling of euphoria

Question 3

Put the routes of administration of drugs in ascending order of speed of absorption/onset of euphoria

Answer 3

Oral < Intranasal (snorting) < Intravenous < Inhalation (smoking)

Question 4

Why is the speed of absorption/onset of euphoria for smoking/inhalation slightly quicker than IV injections?

Answer 4

Smoking brings the drug to the alveoli where it easily crosses the alveoli and enters the pulmonary circulation
There is a shorter distance from the pulmonary circulation to the heart and then to the brain than from the site of IV injection to the heart and then to the brain

Question 5

What is an alkaloid?

Answer 5

Any class of nitrogenous organic compound of plant origin that has profound physiological actions on humans

Question 6

What are the active components of the Cannabis sativa plant?

Answer 6

Cannabinoids (there are over 60 of them in the plant)

Question 7

1) What is the most potent cannabinoid in the plant?
2) What is another important cannabinoid that appears to counteract some of the negative effects of this potent cannabinoid?

Answer 7

Delta-9-tetrahydrocannabinol (Delta-9-THC)

Cannabidiol

Question 8

How has cannabis production changed over the last 10-15 years? Why is this relevant?

Answer 8

There has been an increase in the amount of 9-THC in the cigarette meaning that there is less cannabidiol
This suggests that cannabis production is heading towards being more pro-psychotic

Question 9

Describe the bioavailability of cannabis for the oral and and inhaled routes of administration?

Answer 9

Oral = 5-15% 
Inhalation = 25-35%

Question 10

Describe the accumulation of cannabis in the brain following administration.

Answer 10

Cannabis levels in the brain rise very quickly after administration but, because the brain is highly perfused, the cannabis levels in the brain fall rapidly as well

Question 11

Describe the accumulation of cannabis in fat following administration.

Answer 11

Cannabis (as well as its metabolites) is very lipid soluble so it slowly accumulates in the fat - ratio of concentration in fat to plasma = 10^4 : 1
This means that cannabis will leak from the store in the fat for a long time after administration

Note: intensive accumulation occurs in less vascularised tissues and finally body fat

Question 12

What is an important metabolite of cannabis?

Answer 12

11-hydroxy THC (this is more potent than Delta-9-THC)

Question 13

What happens to this metabolite once it has been produced?

Answer 13

It is excreted in the bile into the GI tract but then it undergoes enterohepatic recycling and re-enters the blood stream where it can exert its physiological effects
Because of this, plasma Delta-9-THC levels are a poor measure of intoxication

Urine excretion (25%)
Gut excretion (65%)

Question 14

Where are the different cannabinoid receptors found?

Answer 14

CB1 – brain (Hippocampus/cerebellum/
cerebral cortex/basal ganglia)

CB2 – peripheral immune cells

Question 15

What type of receptor is the cannabinoid receptor?

Answer 15

Inhibitory G protein coupled receptor (i.e. negatively coupled with adenylate cyclase) => depressive effects

Question 16

Name an endogenous cannabinoid.

Answer 16

Anandamide

Question 17

Summarise the mechanism by which cannabis causes euphoria

Answer 17

Cannabis binds to CB1 receptors expressed by GABA interneurons => removal of the inhibitory influence of GABA interneurons on the dopaminergic neurones of the reward pathway => increased firing
(i.e. inhibiting the inhibition)

Question 18

What area of the brain does cannabis interact with that is linked to its psychotic effects?
What is this part of the brain responsible for?

Answer 18

Anterior Cingulate Cortex

• Involved with performance monitoring with behavioural adjustment in order to avoid losses
• There is hypoactivity in the anterior cingulate cortex in chronic cannabis users

Question 19

What effect does cannabis have on appetite/food intake, and why?

Answer 19

Positive effect on orexigenic neurones in lateral hypothalamus;
1. Presynaptic inhibition of GABA increases MCH neuronal activity
2. Increased orexin
production

Question 20

What effect does cannabis have on the immune system?

Answer 20

Cannabis is a powerful immunosuppressant

Question 21

How does cannabis cause memory loss?

Answer 21

It decreases the production of BDNF (brain derived neurotrophic factor), which is important in the hippocampus in forming memories
In general, cannabis has a depressant effect on the hippocampus

Question 22

How does cannabis cause impaired psychomotor performance?

Answer 22

Depressives effect on the cerebral cortex

Question 23

State and explain another peripheral effect of cannabis

Answer 23

Causes tachycardia, and vasodilation (especially in the conjunctivae - blood shot eyes)

• Cannabis acts via the TRPV1 receptor to cause calcium influx

Question 24

Why is it not possible to overdose on cannabis?

Answer 24

There is very low expression of CB1 in the medulla (which is where you find the cardio-respiratory centres)

Question 25

Up-regulation of endogenous cannabinoids and CB1 receptors is involved in what in terms health and disease?

Answer 25

Multiple sclerosis/pain/stroke (regulatory)

Fertility/obesity (pathology)

Question 26

State 4 drugs that are either cannabinoid agonists or antagonists.

Answer 26

Dronabinol - Delta-9-THC
Nabilone - Delta-9-THC
Sativex - Delta-9-THC + cannabidiol
Rimonabant – CB1 antagonist

Question 27

What can cannabinoid receptor agonists be used for?

Answer 27

Treatment of nausea due to chemotherapy

Question 28

What is Sativex used for?

Answer 28

Symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis

Question 29

What can Rimonabant be used for?

Answer 29

Anti-obesity medication (removed because it was shown to cause depression and suicidal thoughts)

Question 30

Half-life of cannabis?

Answer 30

7 days