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 structure of the central reward pathway.

Answer 2

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

Question 3

Put the routes of administration of drugs in order of speed of absorption.

Answer 3

Smoking > IV > Snorting > Oral

Question 4

Why is smoking 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 are the different classes of the drugs of abuse? Give examples for each

Answer 5

Narcotics/painkillers – e.g. opiate like drugs (heroin)

Depressants – e.g. alcohol, benzodiazepines (valium)

Stimulant – e.g. cocaine, caffeine, nicotine

Miscellaneous - stimulant or depressant with other effects e.g. cannabis

Question 6

What is an alkaloid?

Answer 6

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

Question 7

What are the active components of the Cannabis sativa plant?

Answer 7

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

Question 8

What is the most potent cannabinoid in the plant?

Answer 8

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

Question 9

What is another important cannabinoid that appears to counteract some of the negative effects of the potent cannabinoid?

Answer 9

Cannabidiol

Question 10

How has cannabis production changed over the last 10-15 years?

Answer 10

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 morepro-psychotic

Question 11

What percentage of smoked and eaten cannabis will reach the blood stream?

Answer 11

Smoked - Around 30%, some breathed out, swallowed

Oral - 10% delayed onset, slow absorption, extensive first pass metabolism

Question 12

Describe the accumulation of cannabis in the brain following administration.

Answer 12

Cannabis levels in the brain rise very quickly after administration because the brain is 60% lipids but, because the brain is highly perfused, the cannabis levels in the brainfall rapidly as well

Question 13

Describe the accumulation of cannabis in fat following administration.

Answer 13

The metabolite of THC (11-OH-THC) and THC iteslf are very lipid soluble so it slowly accumulates in the fat. Cannabinoid metabolites accumulate more than the cannabinoids themselves
This means that cannabis will leak from the store in the fat for a long time after administration

Question 14

How long will the effects of cannabis last after smoking a joint?

Answer 14

Around 30 days (because of the storage in adipocytes)

Question 15

What is an important metabolite of cannabis? What are its 2 main different properties to THC?

Answer 15

11-hydroxy THC
this is more potent than Delta-9-THC
but is slightly less lipid soluble

Also THC-COOH which is the inactive metabolite

Question 16

What happens to this metabolite once it has been produced?

Answer 16

It is excreted in the bile into the GI tract but then it undergoes enterohepatic cycling 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

Question 17

Where are the different cannabinoid receptors found?

Answer 17

CB1 – brain

CB2 – peripheral immune cells

Question 18

What type of receptor is the cannabinoid receptor?

Answer 18

G protein coupled receptor – negatively coupled with adenylate cyclase

Question 19

Name one endogenous cannabinoid.

Answer 19

Anandamide

Question 20

Describe how cannabis causes euphoria.

Answer 20

Cannabis binds to CB1 receptors on GABA neurones and inhibits the GABA neurones
This means that they remove the inhibitory influence of GABA neurones on the dopaminergic neurones of the rewards pathway in the VTA, hence there is increased firing of the dopaminergic neurones –> euphoria

This is termed ‘dis-inhibition’

Question 21

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

Answer 21

Anterior Cingulate Cortex

There is hypoactivity in the anterior cingulate cortex in chronic cannabis users

Question 22

What is this part of the brain responsible for?

Answer 22

Performance monitoring and behavioural adjustment in order to avoid losses

Question 23

Which part of the brain does cannabis act on to stimulate food intake?

Answer 23

Lateral hypothalamus

Question 24

What are the two main groups of neurones that are involved in stimulating appetite?

Answer 24

MCH (melanin concentrating hormone) neurones

Orexin neurones

Question 25

What effect does cannabis have on these neurones?

Answer 25

Cannabis inhibits the inhibitory effect of GABA on MCH neurones, thus leading to increased MCH firing
Cannabis also directly stimulates orexin production
This leads to hunger

Question 26

Describe the effect of cannabis on the immune system.

Answer 26

Cannabis is a powerful immunosuppressant

Question 27

How does cannabis cause memory loss?

Answer 27

It inhibits 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 28

How does cannabis cause impaired psychomotor performance?

Answer 28

It depresses the cerebral cortex

Question 29

How does cannabis cause cardiovascular effects?

Answer 29

Cannabis acts via the TRPV1 receptor to cause calcium influx

Question 30

What are the cardiovascular effects of cannabis?

Answer 30

Activating the TRPV1 receptor leads to calcium influx –> tachycardia

Question 31

In which part of the body does cannabis cause a lot of vasodilation?

Answer 31

Conjunctivae (bloodshot eyes)

Question 32

Why is it not possible to overdose on cannabis?

Answer 32

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

Question 33

What is the upregulation of cannabinoid receptors in physiology associated with?

Answer 33

In multiple sclerosis/pain/stroke to reduce the imflammation

Also pathologically increased in obesity

Question 34

State 4 drugs that are either cannabinoid agonists or antagonists.

Answer 34

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

Question 35

What can cannabinoid receptor agonists be used for?

Answer 35

Nabilon - Treatment of nausea due to chemotherapy

Dronabinol - increase appetite in patients with severe weight loss

Question 36

What is Sativex used for?

Answer 36

Treatment for symptom improvement (pain) in adult patients with moderate to severe spasticity due to multiple sclerosis

Question 37

What was Rimonabant be used for?

Answer 37

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

Question 38

How is THC processed in the body?

Answer 38

Converted to 11-hydroxy-THC in the liver

Extensive enterohepatic recycling

25% lost in urine

Question 39

Whats the half life of cannabinoids?

Answer 39

7 days