Lecture 12: cannabis and the brain

Who brought cannabis to the Western world?

William Brooke O’Shaughnessy, an Irish surgeon

What are the effects of cannabis on the body?

• Euphoria

• Fine motor sedation

• Anxiolysis

• Increased appetite

• Increased heart rate and vasodilation

• Deficits in memory and attention

What are the two biologically-active components of cannabis?

Cannabidiol (CBD) and delta9-tetrahydrocannabinol (THC)

What are the two main strains of the cannabis plant?

Cannabis sativa and Cannabis indica (however almost all weed is a hybrid of the two strains)

What is the difference between ganja, weed/bhang, hashish

What part of the cannabis plant they are made from. In order of increasing potency:

Ganja - small leaves and stems

Bhang/weed - dried leaves, flowering shoots, and buds

Hashish - resinous exudes from flower tops

How did researchers in the 1960s figure out THC was a biologically active component of hashish?

They separated out the components of some hashish by molecular weight and injected them into rhesus monkeys

What is the tetrad of dose-dependent behavioural changes associated with THC?

Hypolocomotion, hypothermia, catalepsy and analgesia

Define cannabinoid

Several structural classes of compounds found primarily in the cannabis plant or synthetic molecules

What type of cannabinoid are THC and CBD?

Both phytocannabinoids (as opposed to endocannabinoids)

What is the difference in structure between phytocannabinoids and endocannabinoids?

Phytocannabinoids are structurally similar to THC in that they are multi-ring phenolic compounds, endocannabinoids are fatty acid derivatives

What are synthetic cannabinoids also called?

Cannabimimetics

What are the two main cannabinoid receptors in the body?

CB1 and CB2

What is the main endocannabinoid in the brain? How does it interact with CB1 and CB2?

2-AG, which is a full agonist of CB1 and CB2

How did scientists figure out where cannabinoid receptors were in rat brains?

They made a synthetic radiolabeled ligand

They incubated a slice of rat brain with the ligand and looked at it

They found darker areas (areas of specific binding) which showed that there were specific receptors

Which pain-associated regions contain a lot of CB1 receptors?

PAG, PVM and dorsal horn of spinal cord

Which brain region, associated with appetite, contains a lot of CB1 receptors?

Hypothalamus

Which brain region, associated with reward, emotion and motor function, contains a lot of CB1 receptors?

Basal ganglia

Which brain regions, associated with memory, cognition and emotion, contains a lot of CB1 receptors?

Hippocampus and cortex

Which brain region, associated with motor function, contains a lot of CB1 receptors?

Cerebellum

Why is CB1 found primarily on presynaptic axon terminals?

2-AG acts as a “circuit breaker” at neuronal synapses

What are three benefits of having 2-AG act as a circuit breaker?

Can reduce unpleasant signalling as in pain

Can prevent excitotoxicity

Act on inhibitory neurons in reward pathways, increasing dopamine signalling

Briefly describe the mechanism for 2-AG interactions with CB1

Glutamate is released into the synapse

ECs are a retrograde signal that go BACK across the synapse

ECs bind to presynaptic CB1 receptors

They are taken up into the presynaptic neuron and are broken down by specific enzymes

How do cannabinoids affect synaptic plasticity?

CB1 has normal essential roles in learning and memory

Reducing tonic inhibition allows long-term potentiation to occur and synapses to be strengthened

Interfering with this process is one way THC disrupts short-term memory

How do levels of CB1 receptors change in humans with chronic cannabis use?

Reduced

Is there any evidence that it is possible to fatally overdose on cannabis?

Some studies show cannabis suppresses breathing behaviours especially in rodents

However all cannabis associated fatalities in humans are the result of traffic accidents etc

This is because there aren’t many cannabinoid receptors on brain regions associated with heart rate etc

However THC can be fatal if purified and injected

Where is CB2 expressed and, broadly, what does it do?

It is absent in brain, present in spleen on immune cells

Mediates immune effects of cannabis: anti-oedemic (anti-fluid retention), anti-inflammatory, neuroprotective

Expression increases during immune responses, in pain states, and neurodegenerative disease

What is JHW-08

A fast-acting and longer-acting synthetic cannabinoid

Synthesized in 1999 by John W Huffer for research purposes

Full synthetic process published in the scientific literature so people started making it…

A 2016 psychoactive substances act made a blanket ban on all synthetic cannabinoids and psychoactive substances in the UK

What are some harmful effects of chronic cannabis use?

Associated with psychosis and schizophrenia (no established causal link)

Neurological decline

Anxiety disorders

Abuse, tolerance and dependence

Pulmonary disease associated with smoking

Traffic accidents etc

Give an example of a legal cannabis-based medication that uses THC as its active ingredient

Dronabinol and Nabilone: capsules of THC used to treat chemotherapy-induced nausea and appetite stimulation in AIDS wasting disease in the US and Canada

Give an example of a legal cannabis-based medication that uses CBD as its active ingredient

Epidiolex: liquid CBD used to treat childhood epilepsy syndromes

Give an example of a legal cannabis-based medication that uses THC and CBD as its active ingredients

Sativex (nabiximols) used to treat MS spasticity in several countries including the UK (and MS pain and cancer pain in Israel)

In general, what is the main use of cannabis-based medication? Does it work?

Mainly used to lessen pain but mixed evidence for whether it works

Give a potential medical application for cannabis on a mental health condition

Potential for use treating PTSD, Parkinson’s, Alzheimers, traumatic brain injury and stroke, Tourette’s syndrome