Drugs of Abuse 1 (22.01.2020)

Question 1

Why are certain drugs such as cannabis abused?

Answer 1

• they cause euphoria
• they activate the reward pathway in the brain
• Dopamine release in nucleus accumbens (originating in the ventral tegmental area)

Question 2

Summarise the reward pathway in the brain

Answer 2

• rewarding stimulus (such as food (high glucose) or drugs causes activation of the neurones in the ventral segmental area
• as a result there is domamine release from the terminals of these neurones in the nucleus accumbens
• this leads to a sense of reward
• Mesolimbic dopamine system – Central ‘reward’ pathway

Question 3

What are the main routes of administration for drugs of abuse?

Answer 3

• intranasal (snort)
• oral (eat)
• intra venous (inject)
• inhalation (smoke)

Question 4

Which routes of administration are the fastest and why?

Answer 4

• inhalation: small airways and alveoli. Alveoli are designed to Gove minimal resistance and because of this low resistance and the blood travelling straight to the left side of the heart and then to organs this is th e fastest absorption.
• intra-venous: directly into the veins, has to travel to the heart and through pulmonary circuit to reach brain. Rapid absorption.
• intra nasal: Mucous membranes of nasal sinuses. Slow absorption.
• oral: GI tract, very slow absorption

➡️ Oral < Intranasal < Intravenous < Inhalational

Question 5

How do you classify drugs of abuse?

Answer 5

• Narcotics/Painkillers – opiate like drugs e.g. heroin
• Depressants – ‘downers’ e.g. alcohol, benzodiazepines (valium), barbiturates (slow things down)
• Stimulants – ‘uppers’ e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’) (speed things up)
• Miscellaneous – e.g. Cannabis, Ecstasy (MDMA) ->. cannabis is a depressant but it also fits into other categories. ecstasy xcan be a stimulant but it also has other qualities that makes it hard to classify.

Question 6

What is a cannabinoid?

Answer 6

A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors, which are part of the endocannabinoid system found in cells that alter neurotransmitter release in the brain.

Question 7

What is the cannabis plant called?

Answer 7

Cannabis Sativa

Question 8

How many substances are found in the cannabis plant? (Cannabis Sativa)

Answer 8

> 400 compounds
60 cannabinoids

Most important substances:

• cannabidiol (CBD)
• delta-9 tetrahydrocannabinol (delta-9 THC)

Question 9

What are the different forms and names of cannabis?

Answer 9

= marijuana

• Hashish/Resin – Trichomes (glandular hairs) -> cannabinoids are mainly found in the glandular hairs (hashish is a drug made from the resin of the cannabis sativa plant)
• hash oil via solvent extraction (you can extract it with a solvent and concentrate it)

Question 10

Dosing of cannabis?

Answer 10

• now plants are specifically farmed to increase the amount of THC (in 60s/70s a ‘reefer’ contained 10mg THC but now Skunkweed/Netherweed’ 150mg THC; 300mg THC (+ hashish oil)
• this is important due to dose specific effects:
  
  • there is an increasing risk of negative effects with increasing dose
  • you hit aa ceiling of positive effects sooner, at a lower dose.
  • Initially there was a balance between cannabidiol and delta 9 thc
  • Cannabidiol might be a good thing and might moderate the negative effects of THC
  • in some of the newer plants you may have lost cannabidiol to increase delta-9-THC and therefore have more negative effects

Question 11

Pharmacokinetics of cannabis - how much is bioactive with oral and inhalational RoA?

Answer 11

• Oral – 5-15%; delayed onset/slow absorption; first pass metabolism;
• Inhalation – 25-35%; the deeper you inhale it the higher the bioavailability.
• from an administration point of view bioavailability is irrelevant because you can just titrate up the dose.

Question 12

What is the maximal bioavailability you will get with inhalation as a RoA?

Answer 12

• usually won’t get much better then 25-35%
• won’t be higher than 50% because when you inhale a drug you exhale 50% of it back out almost right away and for that 50% it would have to get in very deep, to the alveoli where absorption is most effective.
• chronic smokers of any drugs inhale deeply because then they ensure that more drug is taken up.

Question 13

What happens with cannabis once it is in the system?

Answer 13

• it is VERY lipid soluble
• it travels through the blood and readily crosses the plasma membrane to enter tissues, those are well perfused tissues
• highly perfused tissues i.e. brain will receive a lot of cannabis very quickly
• low perfusion tissues will receive less and more slowly
• chronic use: massive build up in the adipose tissue (10^5 fat : 1 plasma) despite poor perfusion (2% CO)
• over time there will be a slow leak form fat to blood over time.

Question 14

What happens in chronic cannabis use?

Answer 14

• heavy accumulation in fat
• CO to adipose tissue is very low (~2%) however if you often have cannabis in your blood there will be a heavy accumulation in this tissue that is not well perfused because it is very lipid soluble and prefers fat.
• 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 10^4 : 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 15

Metabolism of cannabis

Answer 15

• phase 1 reaction produces 11-hydroxy-THC -> it is made to uncover a reactive group to make excretion easier however it is a more powerful metabolite than delta 9 THC.
• the liver will conjugate it but it can only conjugate so much of it per unit of time so a part of this active metabolite will end up also in the blood.

Question 16

Excretion of cannabis

Answer 16

Urinary
- 25%

GIT

• 65%
• via bile (excreted into bile, bile projected into gut, excreted)
• however, consider enterohepatic circulation:
• very lipid soluble so once in the gut it is happily reabsorbed and enters the circulation again

Poor correlation between plasma
cannabinoid concentration and degree
of intoxication
-> no info about fat buildup, enterohepatic recycling and 11-OH-THC

Question 17

How much of the brain is fatty tissue? Why is it important in terms of cannabis?

Answer 17

• 60%
• this is important because cannabis happily accumulates there and in chronic use there is a buildup of this depressant in the brain.

Question 18

How long after smoking a cannabis 
cigarette will the effects persist in the body?
- 5 hours
- 12 hours
- 7 days
- 30 days
- 10 years

Answer 18

30 days

(look at the plateau of fat, it starts after about 5 d so it will take some time for that plateau to fall again (slide 21))

-> there is a 30d timespan to detect caannabis in the blood, however you can also detect it in hair.

Question 19

Pharmacodynamics of cannabis: which receptors does cannabis bind to?

Answer 19

• cannabinoid receptors
• GPCRs (Gi/o) which negatively influence adenylate cyclase (coupled to adenylate cyclase -> depress cell activity)
• CB1 receptors: Hippocampus/cerebellum/cerebral cortex/basal ganglia (brain)
• CB2 receptors: on immune cells (peripheral)

Question 20

Pharmacodynamics of cannabis - Euphoria

Answer 20

• cannabis binds to CB1 receptors on GABA-ergic interneurones projecting to the neurones in the ventral tegmenjtum area
• GABA naturally surpasses the reward pathway, drugs often have to turn off GABA to increase firing
• CB1 R – there is DISINHIBITION of GABA in the reward pathway which increases endogenous reward pathway.
• more firing of neurones form VTA to NAcc and more Da release causing feeling of reward.

Question 21

What is an endogenous agonist of the CBR?

Answer 21

Anandamide

Question 22

Cannabis and psychosis/schizophrenia

Answer 22

• The anterior cingulate cortex (ACC)
• Role of ACC - 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.
• involved in error detection
• Involved with performance monitoring with behavioural adjustment in order to avoid losses
• Hypoactivity in cannabis users: Cannabis suppresses this part of the brain, so the ability to monitor and change behavior decreases.
• Does cannabis cause schixophrenia or are schizophrenics more likely to take cannabis.

Question 23

Pharmacodynamics of cannabis in terms of food intake

Answer 23

• Positive effect on orexigenic neurones in lateral hypothalamus
• orexin has a positive effect on hunger
• 1. Presynaptic inhibition of GABA increases MCH neuronal activity
• 2. Increased orexin production (CB1 receptor interaction with orexin)
• caannabis use is linked to food seeking behaviour
• see slide 27

Question 24

Pharmacodynamics of cannabis in terms of the immune system.

Answer 24

• cannabis binds to CB receptors which are found on:
  
  • T lymphocytes (4)
  • B lymphpcytes (1)
  • NK cells (2)
  • Mast cells (3)
• cannabis acts immunosuppressive
• more powerful with some of these cells than others
  => chronic use of cannabis causes increased susceptibility to infection

Question 25

In summary what are the effects of cannabis?

Answer 25

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

Peripheral effects:

• immunosuppressant
• Tachycardia/vasodilation (Conjunctivae!) this is due to TRPV1 receptor activation, different target but this is not sure.
• Medulla – Low CB1 receptor expression (does not cause respiratory depression)

Question 26

BDNF

Answer 26

Brain-derived neurotrophic factor

• key thing that increases hippocampal health and facilitates memory formation

Question 27

What are the medical applications of cannabis?

Answer 27

• delta-9-THC: Dronabinol, Nabilone - agonist(stimulate appetite in AIDS or chemotherapy patients, antiemetics)
• delta-9-THC + CBD: Sativex - agonist (analgesic, neuropathic plain, MS associated pain)
• rimonabant - blocks the effects of cannabinoid it was an anti obesity agent and decreases weight but it wasn’t there for too long but it caused suicides and depression, however very goof as anti-obesity

Question 28

When is an elevation of CB1 receptors seen?

Answer 28

• in conditions such as MS, pain and stroke - here it seems to be protective
• it is also seen in conditions such as obesity and infertility, the more obese the more receptors in adipose tissue and in liver and it seems to contribute to the condition; in particular in male infertility where it decreases testosterone, decrease driving of gonadal function in pituitary, inhibit sperm production - so it also seems to be pathological in that sense.