Drugs of abuse 1: General drugs & Cannabis Flashcards
Why are certain drugs abused?
They induce euphoria (feeling of intense happiness)
How do drugs induce euphoria?
The reward system
- Dopaminergic neurones from the ventral tegmental area (VTA) project to the nucleus accumbens (NAcc)
- Dopamine release at the nucleus accumbens stimulates feelings of reward and happiness
- Essentially this pathway is activated by any stimuli which make you feel happy and rewarded
-
Examples:
- Food
- Money
- Social interaction
-
Examples:
Drugs can also stimulate the reward system in the brain → euphoria

What are the different routes of administration for drugs of abuse?
- Intranasal (snort)
- Oral (eat)
- Inhalational (smoke)
- Intravenous (inject)
Describe how fast the drug would have an effect on the brain with each route of administration.
REMEMBER:
- To have an effect on the brain, the drug needs to enter the systemic circulation
- Arterial part of the circulation as it has to supply the brain
- So the drug which is first absorbed into the bloodstream will reach and have its effect on the brain the fastest
Routes of administration
- Intranasal (snort)
- The drug has to be absorbed through the mucous membranes of the nasal sinuses
- This absorption is slow
- The drug has to be absorbed through the mucous membranes of the nasal sinuses
- Oral (eat)
- The drug has to be absorbed through the walls GI tract
- This absorption is very slow
- The drug has to be absorbed through the walls GI tract
- Inhalational (smoke)
- The drug has to be absorbed through the alveoli
- This absorption is rapid
- The drug has to be absorbed through the alveoli
- Intravenous (inject)
- The drug is injected straight into the veins so doesn’t even need to be absorbed
- Rapid
- The drug is injected straight into the veins so doesn’t even need to be absorbed
Pathway to the brain
Oral, intranasal, IV:
- Once absorbed, the drug enters the venous system
- Or in the case with IV, the drug is directly injected into the venous sytem
- Venous system → RA → RV → lungs → LA → LV → arterial system → brain
- Therefore, the quicker the drug is absorbed into the venous system, the faster the drug will have its effect on the brain
- So out of these 3 routes of administration, fastest → slowest:
- IV → intranasal → oral
Inhalational:
- This is the fastest to have an effect on the brain
- Alveoli → LA → LV → arterial system → brain
- You are skipping the whole venous system → RA → RV part which means that it gets to the lungs faster
What are the different classifications of the drugs of abuse? Give examples for each classification.
-
Narcotics/painkillers - opiate-like drugs
- EXAMPLE:
- Heroin
- EXAMPLE:
-
Depressants (‘downers’)
- EXAMPLES:
- Alchohol
- Benzodiazepines (valium)
- Barbiturates
- EXAMPLES:
-
Stimulants (‘uppers’)
- EXAMPLES:
- Cocaine
- Amphetamine (‘speed’)
- Caffeine
- Metamphetamine (‘crystal meth’)
- EXAMPLES:
-
Miscellaneous
-
EXAMPLES:
- Cannabis
- Ecstasy (MDMA)
-
EXAMPLES:
Describe where the drug cannabis comes from.
Cannabis = marijuana
The whole Cannabis sativa plant contains:
- Over 400 compounds - within which there are…
- Over 60 cannabinoids
- Cannabinoids = the active component which acts on cannabinoid receptors in the body
- Highest concentration of cannabinoids in the trichomes (glandular hairs) of the plant
Drug extraction:
- Trichomes are secretory in function
- Substances secreted by plants is known in general as resin
- Hashish is a cannabis concentrate made from the resin of the cannabis plant
- Hash oil is also a cannabis concentrate, where extraction from the plant involves a solvent
State two major cannabinoids.
Δ9-Tetrahydrocannabinol (Δ9-THC)
- This is the most potent cannbinoid
Cannabidiol
- This moderates some of the negative effects of Δ9-THC
- Protective in function

Describe how the dose of cannabinoids extracted from a Cannabis sativa plant has changed over time. Describe the effect this has on the drug user
Before (60s and 70s):
- From a plant you would be able to extract 10mg of Δ9-THC
Nowadays:
- Various forms of the Cannabis sativa plant have been farmed so that a higher dose of Δ9-THC can be exracted from them - 150-300mg
Increase in Δ9-THC dose = more powerful drug effect
- However, these farmed forms of the plants also have a lower proportion of cannabidiol
- Increased the amount of Δ9-THC at the expense of cannabidiol
- This means that you have essentially lost the protective effect of cannabidiol
Increase in Δ9-THC dose leads to increase in negative effects
- Δ9-THC has negative effects so it makes sense that increase in dose leads to increase in negative effects
- However, the decrease in the proportion of cannabidiol with an increased dose of Δ9-THC means you have reduced protection against the negative effects → increased negative effects
NOTE: Long term cannabis use is associated with decreased performance
What are the main routes of administration of cannabis?
Oral
- Bioavailability: 5-15%
- This is due to first pass metabolism (in GI tract, liver)
- Slow absorption through GI tract → delayed onset
Inhalation
- Bioavailability: 25-30%
- When you inhale a drug, you lose 50% of it through exhalation (i.e. when you exhale)
-
Of that 50% which isn’t lost, you need to inhale deep enough for the drug to reach the alveoli and be absorbed into the bloodstream
- The deeper you inhale, the more drug will reach the alveoli before you have to exhlae again
NOTE: Bioavailability = proportion of unchanged drug that reaches the systemic circulation
Describe the pharmacokinetics of cannabis.
- Cannabis is very lipid soluble
- Fat (adipose tissue) is poorly perfused - receives 2% of CO
- Therefore, cannabis slowly accumulates in fatty tissues as fatty acid conjugates
-
Slow accumulation due to poor perfusion
- Takes time for blood to reach fatty tissue
-
Accumulation due to poor perfusion
- Drug does not get as much opportunity to diffuse back into the bloodstream via fatty tissue**
-
Slow accumulation due to poor perfusion
- Ratio of cannabis concentration - fat : plasma
- 104 : 1
- REMEMBER:
- Cannabis does slowly leak back into the bloodstream
- This allows drug clearance

How long do the effects of cannabis last in the body?
30 days
- This is because cannabis accumulates in fatty tissues and leaks slowly back into the bloodstream, allowing clearance
What is the correlation like between plasma cannabinoid concentration and degree of intoxication?
Poor correlation
- This is due to the accumulation of cannabis in fatty tissue
- 60% of brain content is lipid
- This lipid has a structural function
- It is not available to be metabolised for energy so this proportion stays the same
- Cannabis can accumulate in the fatty tissue in the brain and leak out to affect the brain → intoxication
- Cannabis is much more concentrated in the brain than in the plasma - therefore poor correlation

How is cannabis excreted?
NOTE: THC (Δ9-THC) is the major component (cannabinoid) in the cannabis taken nowadays
- Liver converts THC → 11-hydroxy-THC (more potent)
- 11-hydroxy-THC can be conjugated with bile and be excreted
- So 65% excreted via GI tract
- BUT:
- Intestinal bacteria hydrolyses the bile conjugate, releasing the free drug (THC)
- Since THC is very lipid soluble, it can diffuse back into the blood → enterohepatic recycling
- 25% excreted in the urine
Where does cannabis act in the body?
Cannabis acts on cannabinoid (CB) receptors
-
CB1
- Found centrally
- Hippocampus
- Cerebellum
- Cerebral cortex
- Basal ganglia
- Found centrally
-
CB2
- Found peripherally
- Immune cells - major location but found elsewhere
- Found peripherally
NOTE: These receptors are found as part of the endocannabinoid system in the body, which is involved in a wide variety of physiological processes
What endogenous substance act on the CB receptors?
Anandamide - an endocannabinoid
What types of receptors are CB receptors?
G-protein coupled receptors
- Gi → inhibits adenylate cyclase → decreases cAMP → decreases cellular activity
- Therefore cannabis functions as a depressant

How does cannabis cause euphoria?
- Cannabis stimulates the reward pathway by disinhibition
- Cannabis binds to the CB1 receptor on GABA interneurones
- This inhibits GABA release
- Makes sense as CB receptors are depressant
- So when activated, they would slow down the activity of the GABA interneurones, preventing GABA release
- GABA has an inhibitory effect on the reward pathway
- So if you inhibit the inhibition → increased activity/firing of the reward pathway neurones → increased dopamine release → euphoria

What does the anterior cingulate cortex (ACC) do?
- Involved with performance monitoring and behavioural adjustment in order to avoid losses
- Essentially, the ACC is continously motinoring the changing environment/situation and how this would influence performance
- This allows it to adjust behaviour accordingly
- At a very basic level, it is involved with error detection
- Error detection is part of performance monitoring
- e.g. ‘GREEN’ written in red
- ACC detects this as a condition under which errors are likely to occur so you can essentially be more careful to avoid the error
- EXAMPLE:
- You can drive a car and talk to the passenger at the same time
- But then you enter a narrow mountain road and a heavy storm breaks out (darker and raining)
- The ACC detects this and how this would influence your performance - i.e. it would be harder to drive
- Therefore, you discontinue your conversation in order to better focus your cognitive resources on safe driving - i.e. behavioural adjustment

What is the link between cannabis and the anterior cingulate cortex?
In cannabis users there appears to be hypoactivity in the anterior cingulate cortex → impaired behavioural adjustment
This could explain the link between taking cannabis and psychosis and schizophrenia
-
Psychosis = you interpret reality very differently from those around you
- You might see, hear, or believe things that aren’t real
- Schizophrenia - type of psychosis
What effect does cannabis have on food intake?
Cannabis stimulates food intake - due to positive effect on orexigenic neurones in lateral hypothalamus
Does this by:
- Pre-synaptic inhibition of GABA → increases MCH neuronal activity
- Increasing orexin production
EXPLANATION:
- MCH neurones are present in the lateral hypothalamus so are orexigenic (stimuates appetite)
- Lateral hypothalamus - feeding centre in the brain
- MCH = melanin concentrating hormone - neuropeptide
- GABA neurones synapse with MCH neurones and inhibit MCH neuronal activity
- Cannabis inhibits GABA release (CB1 mediated) → loss of MCH neurone inhibition → increased MCH neuronal activity → increased appetite
- Presynaptic inhibition - because you are inhibiting the presynaptic neurone in the GABA-MCH neurone synapse
- There is also another group of orexinergic neurones in the lateral hypothalamus
- These produce orexin - stimulate appetite
-
CB1 receptors interact with these neurones
- Stimulation of these receptors by cannabis increases activity of these neurones → increased appetite
- Remember CB1 is a depressant so when stimulated, it is depressing something (don’t know what) which leads to increased orexin production

What effect does cannabis have on the immune system?
Cannabis is an immunosuppressant
- It binds to the CB2 receptor on these immune cells:
- Macrophage
- Mast cell
- B-cell
- T-cell
- Natural killer cell
- Cannabis acts as a depressant to decrease cellular activity → decreases activity of these immune cells

List the central effects of cannabis.
- Psychosis, schizophrenia
- Food intake
- Affects lateral hypothalamus
- Memory loss
- Affects (i.e. depresses activity of) limbic regions
- Hippocampus - involved in memory formation
- Amnestic effects due to decreased BDNF (Brain Derived Neurotrophic Factor)
- BDNF is generally important in the nervous to support the neuronal survival, neuronal growth and synapse formation
- This is important in the hippocampus - synaptic plasticity (change) is required for memory formation
- So reduced BDNF acting on the hippocampus → deterioration of hippocampal function → memory loss
- Affects (i.e. depresses activity of) limbic regions
- Psychomotor performance (i.e. conscious movement)
- Affects cerebral cortex - depresses activity
List the peripheral effects of cannabis.
- Immunosuppression
- Tachycardia and vasodilation
- This is via interaction with a different receptor - TRPV1
- Cannabis activates the TRPV1 receptor which leads to tachycardia and vasodilation
- Tachycardia probably by stimulation of calcium influx through the ionotropic receptro (ion channel)
- Vasodilation - activation of the receptor stimulates release of a vasodilator
- Vasodilation is particularly seen in the conjunctivae (lines inside of eyelids and covers the sclera)
- This leads to bloodshot eyes
Describe CB1 receptor expression in the medulla. Explain why this is important.
The medulla has a low CB1 receptor expression
- The medulla contains the respiratory and cardiovascular control centre
- So if you had high CB1 expression, cannabis would depress the activity of these centres → death
- BUT due to low receptor expression in the medulla, cannabis cannot depress the activity of these centres - not capable of supressing cardiorespiratory control
- Therefore, you cannot overdose on cannabis to the point where you can kill yourself
In what disease states are CB receptors upregulated.
This can either be:
- Regulatory
- Pathological
Regulatory
- This has a protective effect against the diesease
- Seen in these conditions:
-
Multiple sclerosis
- Demylinating disease - due to autoimmunity
- Therefore, immunosuppressive effects by CB receptor upregulation would be useful
-
Pain
- CB1 receptors present within the nervous system - within structures involved in the processing and perception of pain
- CB receptors - depressant affect → can lead to pain depression
-
Stroke
- Ischaemia in the brain can trigger inflammation
- So immunosuppressive effects by CB receptor upregulation would be neuroprotective
-
Multiple sclerosis
Pathological
- This contributes to the disease
- Seen in these conditions:
-
Fertility (i.e. pathology = infertility)
- Particularly male infertility
- CB receptor upregulation:
- Decreases testosterone
- Inhibits pituitary gland (i.e. HPG axis)
- Interferes with sperm production
-
Obesity
- CB1 receptors upregulated in adipose tissue (on adipocytes) and the liver (on hepatocytes)
- This seems to directly contribute to the development of obesity
-
Fertility (i.e. pathology = infertility)
NOTE: Explanations of each condition are extra
State some drugs which affect the CB receptor and their uses.
CB receptor agonists:
- ∆9-THC (synthetic)
-
Dronabinol
- Anti-emetic (treats nausea and vomiting) in patients undergoing chemotherapy
- Used to treat loss of appetite and weight loss in people who have acquired immunodeficiency syndrome (AIDS)
- Nabilone
-
Dronabinol
- ∆9-THC and cannabidiol (synthetic)
-
Sativex
- Symptom improvement in adult patients with moderate to severe spasticity
- Pain control (spasticity causes pain)
-
Sativex
These are used to treat the diseases in which CB receptor upregulation has a regulatory (protective) effect
CB receptor antagonists:
-
Rimonabant
- Anti-obesity agent - no longer available as it was associated with suicide
These are used to treat the diseases in which CB receptor upregulation has a pathological (negative) effect

In terms of CB receptor activity, what other drug is relevant?
Fatty acid amide hydrolase inhibitor
- Fatty acid amide hydrolase breaks down anandamide
- So by inhibiting this, you have more anandamide (an endogenous cannabinoid) to act on and stimulate the CB receptor
- So it would essentially have the same effect as a CB receptor agonist
- Possible use - treatment of chronic pain