Drugs of Abuse - Cannabis

Question 1

What is the reward pathway?

Answer 1

mesolimbic dopamine system in the brain

The reward pathway is a collection of dopaminergic neurones that originate in the ventral tegmental area (this is where the cell bodies are), and project down to the ventral striatum (in particular, an area called the nucleus accumbens)

Question 2

How do stimuli induce reward in the reward pathway?

Answer 2

The reward dopaminergic neurone originates in the ventral tegmental area, and projects to the nucleus accumbens to release dopamine.

Dopamine release in this area causes the feeling of reward. It is an endogenous system.

Stimuli (e.g food/exercise) activate this pathway to cause dopamine release. This is the system that most drugs of abuse HIJACK.

Question 3

What is euphoria?

Answer 3

excessive dopamine release within the nucleus accumbens

Question 4

What are the routes of administration of drugs?

Answer 4

Snort (intranasal) -> drug enters nasal sinus -> venous drainage -> lung -> heart -> brain
- Mucous membranes of the nasal sinuses will slow absorption

Eat or drink (oral) -> stomach -> small intestine -> portal system -> liver -> heart -> brain
- There is very slow absorption due to the GI tract

Smoke (inhalational) -> lungs (right next to the heart) -> heart -> brain
- Rapid absorption (seconds)

Inject (intravenous) -> vein -> heart -> brain
- Rapid absorption (seconds)

Question 5

Which route of administration is the fastest?

Why?

Answer 5

Small difference in the time it takes for drugs to act with intravenous and inhalational administration - inhalation is faster because the lungs are right next to the heart

Additionally, the alveoli are not much of a barrier to diffusion

Inhalation -> alveoli -> venous drainage -> heart -> up to the brain (via the aorta)

Question 6

What are the classifications of drugs of abuse?

Answer 6

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 7

What are cannabinoids?

Answer 7

the compounds that produce the high effect when smoking cannabis

most potent and powerful cannabinoid is Δ9-tetrahydrocannabinol (Δ9-THC)

most concentrated in the glandular hairs of the plant (trichomes) – HASHISH/RESINS

• Cannabidiol: believed to have a protective effect from the negative effects by THC

Question 8

Over the last few decades the potency of cannabis has become much greater. Why is this relevant?

Answer 8

More recent versions of cannabis are far more concentrated in Δ9-THC (150mg/300mg + hashish oil)

Delta-9 THC seems to be more associated with some of the negative effects of cannabis.

As you increase the dose of THC, a greater effect is seen (in terms of BOTH positive symptoms and negative symptoms), however the effect is MUCH GREATER in terms of negative symptoms.

Question 9

What are the common routes of administration of cannabis?

Answer 9

two most common routes are eating (oral) or smoking (inhalation)

• Oral: 5-15% of dose enters bloodstream – delayed onset/slow absorption (first pass metabolism)
• Inhalation: 25-35% of dose enters bloodstream
• Anything inhaled suffers from about 50% loss automatically because only about 50% gets far enough down into the lungs to diffuse into the bloodstream. Lots of it is breathed back out, much of it won’t be absorbed

Question 10

Which tissues does cannabis diffuse into?

Answer 10

Cannabis is very lipid soluble - it accumulates in poorly perfused fatty tissues

MOST OF THE CANNABIS GOES TO VERY WELL PERFUSED TISSUES - however, adipose tissue receives a bit of CO -> so very lipid soluble drugs can diffuse into fat

Intensive accumulation occurs in less vascularised tissues and finally in body fat (major long-term storage site), resulting in concentration ratios between fat and plasma of up to 10^4:1

• The brain is a very fatty tissue, so if you chronically use cannabis, it will accumulate in the brain

Question 11

What are the metabolites of THC?

Answer 11

11-hydroxy-THC (more potent than delta9- THC)

Question 12

How is THC metabolised?

Answer 12

A large amount of cannabis is secreted by the bile (enterohepatic recycling)

goes down the bile duct -> small intestine -> POTENTIAL REABSORPTION

• 65% of 11-hydroxy-THC is secreted into the gut, which is then heavily reabsorbed back into the system

EVENTUALLY, you WILL clear the cannabis (urine loss accounts for 25%)

Question 13

How long do the effects of smoking a cannabis cigarette persist?

Answer 13

around 30 days

Question 14

What is the body’s endogenous cannabinoid system?

Answer 14

body produces cannabis-like substances e.g endogenous anandamide

Question 15

What are the targets of endogenous andandamide?

Where are the found?

Answer 15

CANNABINOID RECEPTORS (Gi-protein coupled)

• CB1 RECEPTORS: predominantly brain (hippocampus, cerebellum, cerebral cortex, basal ganglia
• CB2 RECEPTORS: predominantly on IMMUNE CELLS in the periphery

Question 16

What are the actions of andandamide and cannabis?

Answer 16

binds to receptors -> G-protein is negatively coupled to adenylate cyclase

• Cannabis is a depressant at cellular level -> DOWNREGULATES adenylate cyclase

Question 17

How does cannabis cause euphoria?

Answer 17

Stimulation of the CB1 receptor will switch off and blocks GABA transmission. GABA suppresses the reward pathway – when the reward pathway needs to be activated, GABA is inhibited. Cannabis HIJACKS this system.

There are lots of CB1 receptors on GABA neurones. Cannabis binds -> reduces firing rate of GABAergic neurones (depressant) -> dopaminergic neurone firing increases -> euphoria

Question 18

How can cannabis cause psychosis ( and schizophrenia)?

Answer 18

The anterior cingulate cortex (ACC) is a part of the brain that’s important in error detection and is very important in terms of monitoring behaviour. The ACC is heavily involved with performance monitoring with behavioural adjustment in order to avoid losses (to ensure that good things happen).

In cannabis users, we see hypoactivity in the ACC. Cannabis users will have a problem adjusting their behaviour appropriately – this is one element of psychosis

Question 19

How does cannabis use cause an increased appetite?

Answer 19

Cannabis has a positive effect on orexigenic neurones in lateral hypothalamus.

The arcuate nucleus has two populations of neurone: one that stimulates appetite (AgRP) and one that inhibits appetite (POMC)

1. Presynaptic inhibition of GABA increases MCH neuronal activity
2. Increased orexin production

Cannabis works in the lateral hypothalamus to upregulate the appetite system.

Cannabis switches off GABA -> more firing of MCH. Cannabis also has a direct stimulatory effect on appetite increasing neurones.

Question 20

What is chronic cannabis use associated with?

Answer 20

immunosuppresancy

CB2 receptors are found in the periphery on IMMUNE CELLS -> down regulation of immune response

Cannabis affects the activity of NK cells, macrophages, mast cells, T lymphocytes and B lymphocytes

• Chronic cannabis users have an impaired immune system

Question 21

What are the negative effects of cannabis use?

Answer 21

• Psychosis
• Schizophrenia
• Food intake (Hypothalamus)
• Memory loss – Limbic regions (Amnestic effects/↓ BDNF)
• Psychomotor performance – Cerebral cortex

Peripheral effects:

• Immunosuppressant
• Tachycardia
• vasodilation (conjunctivae – bloodshot eyes)

Question 22

Why is it difficult to die from cannabis?

Answer 22

very low CB1 receptor expression in medulla - contains cardio-respiratory centre

cannabis doesn’t have profound effect in medulla unlike alcohol and nicotine

Question 23

What are some medical applications of cannabis?

Answer 23

There is upregulation of CB receptors in many disease processes e.g. multiple sclerosis/ pain/stroke – regulatory effect – CB receptors are trying to compensate for the disease process)

In some cases, the upregulation of CB receptors is directly contributing to the pathology (fertility/obesity)

1. Dronabinol and nabilone have a primary use to either prevent nausea in chemotherapy patients or to stimulate appetite in AIDS patients or cachectic patients
2. Sativex is an analgesic
3. Rimonabant was one of the first anti-obesity agents to target the cannabinoid receptor. It was decent, but the problem was its propensity to cause depression, and suicide (so it was pulled)

Question 24

What enzyme breaks down endogenous cannabinoids?

Answer 24

fatty acid amide hydrolase inhibitors