13. Drugs of abuse 1 (cannabis)

Question 1

why do people abuse drugs?

Answer 1

for the reward pathway (mesolimbic dopamine system)

Question 2

what is the reward pathway?

Answer 2

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

dopamine release in this area causes the feeling of reward

Question 3

what different stimuli induce reward?

Answer 3

• food

- exercise

Question 4

what are the different routes of administration?

Answer 4

• snort (intranasal): drug enters nasal sinus –> venous drainage –> lung –> heart –> brain
  o Mucous membranes of the nasal sinuses will slow absorption
• eat or drink (oral): stomach –> small intestine –> portal system –> liver –> heart –> brain
  o There is very slow absorption due to the GI tract
• smoke (inhalational): lungs (right next to the heart) –> heart –> brain
  o Rapid absorption (seconds)
• inject (intravenous): vein –> heart –> brain
  o Rapid absorption (seconds)

Question 5

how are drugs classified?

Answer 5

• narcotics/painkillers - opiate like drugs (e.g. heroin)
• depressants - ‘downers’ (e.g. alcohol)
• stimulants - ‘uppers’ (e.g. cocaine, caffeine)
• miscellaneous (e.g. cannabis, ecstasy)

Question 6

why is inhalation the fastest route of drug administration to impact the brain?

Answer 6

• lungs are right next to the heart

- the alveoli are not much of a barrier to diffusion

Question 7

what produces the high effect when smoking cannabis?

Answer 7

cannabinoids which make up 15% of compounds in the cannabis sativa plant

Question 8

where in the plant are cannabinoids more concentrated?

Answer 8

the glandular hairs of the plant (trichomes)

Question 9

where does the version of cannabis ‘hashish/resin’ come from?

Answer 9

the trichomes

Question 10

where does the version of cannabis ‘hash oil’ come from?

Answer 10

solvent extraction

Question 11

what is the most potent cannabinoid?

Answer 11

Δ9-tetrahydrocannabinol (Δ9-THC)

Question 12

what is the effect of cannabidiol on THC?

Answer 12

protective effect from the negative effects of THC

Question 13

how has the dosing of cannabis changed over the years?

Answer 13

• potency has increased

- attempts to concentrate THC to increase effects (10mg in 60s to 150mg nowadays)

Question 14

what are the routes of administration of cannabis?

Answer 14

• oral: 5-15% of dose enters bloodstream
• inhalation: 25-35% of dose enters bloodstream (50% loss automatically because only 50% gets far enough down into the lungs to diffuse into the bloodstream and lots is breathed out)

Question 15

describe the pharmacokinetics of cannabis

Answer 15

• 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

Question 16

what happens to chronic cannabis smokers?

Answer 16

• build up in the fatty tissue (concentration ratios between fat and plasma up to 10^4:1)
• slow leakage back into the blood

Question 17

what are the cannabis metabolites?

Answer 17

• 11-hydroxy-THC (more potent than Δ9-THC) is a metabolite formed in the liver

Question 18

what happens to cannabis metabolites in the body?

Answer 18

• a large amount is secreted by bile (enterohepatic recycling)
• bile duct –> SI –> potential reabsorption

Question 19

what does the recycling of cannabis metabolites mean?

Answer 19

there is a very poor correlation between plasma cannabinoid concentration and degree of intoxication (worse in chronic users)

Question 20

what is the main concern with chronic users?

Answer 20

the brain is a fatty tissue so chronic use leads to accumulation in the brain

Question 21

after smoking a cannabis cigarette how long do the effects persist in the body?

Answer 21

30 days

Question 22

what are the pharmacodynamics of cannabis?

Answer 22

• the body produces cannabis-like substances –> endogenous anandamide which behaves like cannabis
• the targets for anandamide are cannabinoid receptors (Gi-protein coupled):
• -> CB1 receptors: mostly in brain
• -> CB2 receptors: mostly on immune cells in the periphery

Question 23

how does cannabis/anandamide act on receptors?

Answer 23

binds to receptors –> G-protein is negatively coupled to adenylate cyclase –> downregulates adenylate cyclase (depressant at cellular level)

Question 24

how is euphoria induced by cannabis?

Answer 24

• stimulation of the CB1 receptor switches off and blocks GABA transmission (GABA suppresses reward pathway)
• there are lots of CB1 receptors on GABA neurones
• cannabis binds –> reduces firing rate of GABAnergic neurones (depressant) –> dopaminergic neurone firing increases –> euphoria

Question 25

what causes psychosis after cannabis use?

Answer 25

• the anterior cingulate cortex in the brain is important in error detection and monitoring behaviour (allowing behavioural adjustments to avoid losses )
• in cannabis users there is hypoactivity in the ACC so users struggle to adjust their behaviour appropriately

Question 26

why is cannabis use associated with increased appetite?

Answer 26

in the hypothalamus there are 3 regions involved in food intake - the arcuate nucleus (responds to peripheral signals), ventromedial hypothalamus (mostly inhibits food intake), lateral hypothalamus (mostly stimulates food intake)

cannabis acts on the lateral hypothalamus to enhance feeding drive by increasing MCH neurones and orexin neurones and switching off GABA

Question 27

how is cannabis use associated with immunosuppresancy?

Answer 27

• CB2 receptors are found in the periphery on immune cells
• cannabis affects NK cells, macrophages, mast cells, T and B lymphocytes
• this down regulates the immune system

Question 28

outline the effects of cannabis use

Answer 28

• euphoria
• psychosis
• schizophrenia
• increased appetite
• memory loss
• immunosuppressant (peripheral)
• tachycardia/vasodilation (peripheral) –> conjuctivae (bloodshot eyes)

Question 29

why is it difficult to die from cannabis use?

Answer 29

• there aren’t many CB2 receptors expressed in the medulla
• the medulla contains the cardio-respiratory centre
• alcohol/heroin have profound effects in the medulla which can lead to death

Question 30

what is the medical application of cannabis?

Answer 30

• there is upregulation of CB receptors in many disease processes
• this can be both positive and negative
• -> MS, stroke, pain: CB receptors increase which helps regulate disease
• -> fertility, obesity: CB receptor concentration increases as adipose tissue builds up

Question 31

what drugs are legalised versions of cannabis?

Answer 31

AGONISTS

• dronabinol: to prevent nausea for chemo patients or to stimulate appetite in AIDS/cachetic patients
• nabilone: to prevent nausea
• sativex: analgesic

Question 32

what does rimonabant do?

Answer 32

ANTAGONIST

anti-obesity agent that reduces appetite and weight gain (however has been pulled because of links to depression/suicide)