Drugs of abuse 1/general

Question 1

What is another name for the drugs of abuse

Answer 1

Psychoactive drugs

Question 2

Essentially, why are psychoactive drugs abused

Answer 2

To cause euphoria- they do this by hijacking (predominately dopaminergic) reward pathways in the brain.
mesolimbic dopaminergic pathway – the central reward pathwa

Question 3

Outline the central reward pathway

Answer 3

Medial forebrain bundle (myelinated fibres) → Ventral tegmental area (VTA)- dopaminergic neurones. → Nucleus Accumbens (NAcc)

Dopamine release from NAcc vital for ‘rewarding’ effect (End point for drugs of abuse)

Question 4

Outline the methods of administration for the drugs of abuse

Answer 4

§ Methods of administration:

o Intranasal – slow absorption.

§ Mucous membranes of nasal sinus.- gets into venous system this way- right side of heart- pulmonary circulation- left side of heart – brain

o Oral – very slow absorption.- stomach- S.I- hepatic portal system – liver -right side of heart — etc

o Inhalational – rapid absorption.

o Intravenous – rapid absorption.

Question 5

Why is smoking quicker than I.V

Answer 5

Smoking brings the drug to the alveoli where it easily crosses the alveoli and enters the pulmonary circulation ( the alveoli are designed to filter everything)

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 6

For the various drug administration routes, which administration routes will result in a faster onset of euphoria

Answer 6

Ascending order on onset of euphoria – Oral < Intranasal < IV < inhalational

Question 7

Outline the different classifications for the drugs of abuse

Answer 7

Narcotics/Painkillers – opiate like drugs e.g. heroin

Depressants – ‘downers’
e.g. alcohol, benzodiazepines (valium), barbiturates

Stimulants – ‘uppers’
e.g. cocaine, amphetamine (‘speed’), caffeine
metamphetamine (‘crystal meth’)

Miscellaneous – e.g. Cannabis, Ecstasy (MDMA)

Question 8

Why is cannabis classed as miscellaneous

Answer 8

It has various pharmacological properties
such as- hallucinogenic, depressant

Ecstasy has hallucinogen and stimulant properties.

Question 9

Where does cannabis come from

Answer 9

§ The cannabis is the plant, the hashish/resin is the trichomes (glandular hairs that contain the highest concentration of THC) and the hash oil is the solvent extract.

Question 10

What are the active components of the cannabis sativa plant

Answer 10

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

Over 400 other compounds found in Cannabis Sativa.

Question 11

What are the key cannabinoids

Answer 11

§ Cannabis contains over 400 compounds with >60 being cannabinoids.
o Delta9-THC is the most potent cannabinoid. (THC= Tetrahydrocannabinol)
o Positive aspects of smoking weed are from cannabidiol – experts believe a balance between these two (cannabidiol vs. delta9-THC) is needed.

Question 12

How has the dosing of THC in cannabis changed

Answer 12

60’s + 70’s: ‘Reefer’ – 10mg THC

21st Century: ‘Skunkweed/Netherweed’

	- 150mg THC
	- 300mg THC (+ hashish oil) 

This increase in THC has been at the expense of cannabidiol- which is thought to offset the negative effects of THC.
o The negative effects are more pronounced than the positive effects
Hence cannabis production is becoming more pro-psychotic.

Question 13

Describe the difference in bioavailability of the different routes of administration of cannabis

Answer 13

Oral – 5-15% reaches the bloodstream
delayed onset/slow absorption
first pass metabolism

Inhalation – 25-35% reaches the bloodstream
The rest is exhaled or not reached the lungs due to shallow inspiration.

Route of administration massively influences the bioavailability of the drug.

Question 14

Describe the accumulation of cannabis in different tissues over a period of time

Answer 14

Cannabis is very lipid soluble
However, the fat is a very poorly diffused tissue, and so the cannabis will mostly accumulate in the highly perfused tissues (i.e the brain).
However, as the brain is highly perfused, it will also leave the brain just as easily, so its accumulation in the brain rises and falls rapidly.
As it is very lipid soluble, but fat is poorly perfused (2% of cardiac output)- the cannabis will slowly accumulate in the fatty tissue.
The cannabis stored in fat- can also re-enter the bloodstream- complicating its pharmacokinetics.

Question 15

Describe the cannabis stored in fatty tissue

Answer 15

Subsequently, intensive accumulation occurs in less vascularised tissues and finally in body fat, the major long-term storage site, resulting in concentration ratios between fat and plasma of up to 104 : 1. The exact composition of the material
accumulated in fat is unknown, among them being unaltered THC and its hydroxy metabolites. A substantial proportion of the deposit in fat seems to consist of fatty acid conjugates of 11-OH-THC.

Question 16

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

Answer 16

Around 30 days (because of the storage in adipocytes)

Question 17

Describe how cannabis is metabolised in the liver

Answer 17

Phase 1 reactions normally remove the reactive functional group, to then conjugate it in phase 2 reactions to make the compound more soluble and therefore easier to excrete.
However, in phase 1 metabolism, cannabis is metabolised to 11-hydroxy-THC, which is more potent than THC.

Question 18

What happens to this metabolite of cannabis produced by the Liver

Answer 18

It is excreted in the bile into the GI tract but then it undergoes enterohepatic cycling (as it is lipid soluble) and re-enters the blood stream where it can exert its physiological effects

Question 19

Summarise the excretion of cannabis

Answer 19

E: 65% excreted as bile, 25% cleared in urine; enterohepatic recycling occurs; persists in body for 30 days

Question 20

Describe the correlation between plasma cannabinoid concentration and degree of intoxication seen in the user

Answer 20

Poor correlation between plasma
cannabinoid concentration and degree
of intoxication

Question 21

Explain the poor correlation between cannabinoid correlation and the degree of intoxication seen in the user

Answer 21

Brain 60% lipid content – structural i.e. not available to be metabolised for energy.
Lots of cannabinoids stored in adipocytes
Some will exist in more potent form
Some will be undergoing enterohepatic recycling
Therefore there is a lot more going on than the measurement of THC levels suggest.
Hair is really soluble- so THC can also be detected in the hair follicles.

Question 22

What are the receptors for cannabinoids

Answer 22

CB1 receptors (central)
Hippocampus/cerebellum/
cerebral cortex/basal ganglia

CB2 receptors (peripheral) 
Immune cells

Question 23

What type of receptor is the cannabinoid receptor

Answer 23

G protein coupled receptor – negatively coupled with adenylate cyclase
This is how it exerts its depressant effects.

Question 24

Which endogenous molecule binds to the CB receptors

Answer 24

Anandamide
Produced from cholesterol metabolism and breakdown of the cell membranes.
arachidonic acid derivative

Question 25

Describe how cannabis can lead to euphoria

Answer 25

Cannabis binds to CB1 receptors on GABA neurones and inhibits the GABA neurones (these GABA neurones are interneurones and inhibit dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens.

This means that they remove the inhibitory influence of GABA neurones on the dopaminergic neurones of the rewards pathway, hence there is increased firing of the dopaminergic neurones à euphoria

Question 26

What area of the brain does cannabis interact with that produces the psychotic symptoms

Answer 26

Anterior Cingulate Cortex

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

Question 27

Describe the role of the anterior cingulate cortex

Answer 27

Error Detection
GREEN

Involved with performance monitoring with behavioural adjustment in order to avoid losses

Hypoactivity in cannabis users

In changing environments we constantly need to adapt our behaviour by detecting and focusing on the goal-relevant information and selecting the most appropriate behaviour. For example, consider the ability to drive a car while simultaneously engaging in a discussion with a passenger. If we enter a narrow mountain road and a heavy storm breaks out, we might feel the need to discontinue our conversation in order to better focus our cognitive resources on safe driving.

Question 28

Summarise the regulation of food intake

Answer 28

Signals from leptin, ghrelin etc into arcuate nucleus
Two sets of nuclei in arcuate nucleus:
NPY -orexogenic
POMC- anorexogenic

Both of these nuclei project to the ventromedial hypothalmus to the MC4R- which (if stimulated) will lead to catbolism
NPY via AgRP -WILL INHIBIT M4CR
POMC via a-MSH will stimulate M4CR

Also two nuclei in the lateral hypothalamus:
MCH- anabolic
Orexin- anabolic

POMC wil inhibit these via GABA
NPY will stimulate these

Question 29

Describe how cannabis increases food intake

Answer 29

 Cannabis has 2 actions on the lateral hypothalamus:
o Pre-synaptic inhibition of GABA  increases MCH (Melanin Concentrating Hormone) neuronal activity.
o Increase orexin production.
 This acts to increase hunger. via CB1 receptors on orexin nuclei.

Question 30

Describe the immunosupressant effects of cannabis

Answer 30

	Cannabis acts to depress the immune system by agonising CB2Rs on the following:
o	Macrophage.
o	Mast cell.
o	B-cell.
o	T-cell.
o	Natural Killer cell. 

Reduce their function, activity, and proliferation

Question 31

What are the psychological effects of cannabis

Answer 31

Effects on perception; colours seem brighter, music more vivid, emotions more poignant. Perceived time goes faster than clock time.

Question 32

What are the effects of cannabis on psychomotor performance

Answer 32

Psychomotor performance – Cerebral cortex

Slow reaction times, motor incoordination, defects in short term memory

Question 33

Describe the amnesic effects of cannabis

Answer 33

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 34

Summarise the peripheral effects of cannabis

Answer 34

Immunosuppressant

Tachycardia/vasodilation
(Conjunctivae!)

Medulla – Low CB1 receptor expression

Question 35

Describe the CVS effects of cannabis use

Answer 35

Tachycardia up to 160 beats/minute
Widespread vasodilation
Reddening of the conjunctivae – a characteristic sign of cannabis use (due to vasodilation)
Postural hypotension and fainting may occur
Risk factor for severe mental illness!

Question 36

Explain how cannabis causes its cardiovascular effects

Answer 36

Cannabis acts via the TRPV1 receptor to cause calcium influx

Activating the TRPV1 receptor leads to calcium influx à tachycardia and vasodilation.

Question 37

Why is it important to remember that there are low numbers of CB1 receptors in the medulla

Answer 37

Note – the medulla has a LOW CB1R expression and this means that the cardio-respiratory centre is not affected much so it is impossible to overdose on cannabis.

Question 38

Compare the physiological and pathological up-regulation of CB recptors

Answer 38

 There is upregulation of CBRs in:
o MS/pain/stroke patients – to regulate pain.
o Fertility/obesity – this is pathologic and may contribute to obesity and infertility- i.e by reducing testosterone levels in males or release of gonadotrophin

Question 39

Describe the link between endocannibinoids and obesity

Answer 39

Endocannabinoids and CB1 receptors are up-regulated in the liver and adipose tissue in various forms of experimental as well as in human obesity. An up-regulation of CB1 receptors has been also reported in adipose tissue of genetically obese compared with lean mice, and elevated endocannabinoid levels have been detected in adipose tissue of obese compared with lean patients.

Question 40

State four drugs that are cannabinoid agonists or antagonists

Answer 40

Dronabinol - D9-THC

Nabilone - D9-THC

Sativex - D9-THC + cannabidiol

Rimonabant – CB1 antagonist

Question 41

Describe the uses of nabilone or dronabinol

Answer 41

nabilone, is sometimes used clinically for nausea and vomiting caused by cytotoxic chemotherapy if this is unresponsive to conventional antiemetics
Dronabinol is used to treat nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type of nausea and vomiting without good results. Dronabinol is also used to treat loss of appetite and weight loss in people who have acquired immunodeficiency syndrome (AIDS).

Question 42

Describe the uses of Sativex

Answer 42

Cannabis extract (sativex) is used to treat spasticity in patients with multiple sclerosis

Question 43

What was rimnonabant used for

Answer 43

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

Question 44

What will inhibit the production of endocannibinoids

Answer 44

Fatty acid amide hydrolase inhibitor

Synthetic inhibitors of endocannabinoid uptake and/or metabolism have shown potentially useful effects in animal models of pain, epilepsy, multiple sclerosis, Parkinson’s disease, anxiety and diarrhoea.

Question 45

Describe some other important things to remember about this lecture

Answer 45

Metabolised in the liver. A major metabolite is 11-hydroxy-THC (a potent cannabinoid itself). Over 20 other metabolites are known.
Tissue half-life of cannabis = 7 days