- Long-lasting, takes a while to kick in - Routes: smoking/oral (add to food, edibles) - Orally → 30 minutes-2h to develop, lasts for 4-8h - Subject to conjugation n enterohepatic circulation, prolonging duration - Conjugation - Phase 2 metabolism - Grps added to it to to make it more polar - Enterohepatic circulation - Secreted in the bile - Goes back into the gut n reabsorbed - Prolongs the half life - Lipophilic - Stored in the body fat THUS - Can be detected weeks after smoking - Company drug test

Lecture 13: Cannabinoids Flashcards by Lyn Hartono

Central effects of THC

Impairment of
- STM
- Motor coordination → drowsy
- Cognition
Altered sense of time
Mood changes (euphoria/dysphoria)
Catalepsy (trance like state)
Hypothermia
- Can be used as a measure of THC
Analgesia
Antiemetic
Appetite increase
- Useful for cancer treatment

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Peripheral effects of THC

Tachycardia
- Even modest doses 20 -30 BPM
- May increase the chance of MI esp in older people and those with heart problems are at higher risk.
Intraocular pressure (IOP)
- Vasodilation → opens blood vessels in the eye → bloodshot eyes
Fall in IOP
Bronchodilation

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THC pharmacokinetics

Long-lasting, takes a while to kick in
Routes: smoking/oral (add to food, edibles)
- Orally → 30 minutes-2h to develop, lasts for 4-8h
Subject to conjugation n enterohepatic circulation, prolonging duration
- Conjugation
  - Phase 2 metabolism
  - Grps added to it to to make it more polar
- Enterohepatic circulation
  - Secreted in the bile
  - Goes back into the gut n reabsorbed
  - Prolongs the half life
Lipophilic
- Stored in the body fat THUS
  - Can be detected weeks after smoking
  - Company drug test

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Describe the cannabis pilot experiment

9 pilots, current cannabis users, received a cigarette containing 20 mg THC.
After smoking CHT cigarette, significant reduction in performance
- Long-lasting effects -> errors kept persisting even 24h after
Pilots were unaware their performance is impaired
Similar effects to ethanol
Lasts much longer n won’t notice the errors
- Why?
CONCLUSION: cannabis can impair complex tasks over long periods

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Describe the initial hypotheses regarding the mode of action of THC and the discovery of the first cannabinoid receptor

Mode of Action Hypotheses:
- THC is highly lipophilic → initially thought it might change membrane properties (similar to GA) or act at IC receptors.
- Initially considered possibilities:
  - Dissolving in the membrane (lipid soluble) and affecting membrane fluidity.
  - Passing through the membrane and acting on intracellular receptors within the cell.
Discovery of Cannabinoid Receptor:
- The first cannabinoid receptor was discovered in 1988.
- Originally, there was speculation about cannabinoids binding to receptors inside the cell.

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Explain the experimental approach used to identify cannabinoid receptors and the characteristics observed during the process.

Study conducted using a tritium-labelled cannabinoid analogue CP-55,940 along with a cold ligand.
THC (active compound) outcompeted the labelled ligand, indicating binding specificity.
Binding was saturable, suggesting the presence of a specific binding site.
- If non-specific, binding would increase infinitely
- Can’t saturate if there isn’t a specific binding site
- No Vmax
GTP analogs were used to alter the receptor’s affinity, indicating that the protein involved is a GPCR.
The conversion of GTP or GDP changed the affinity of the receptor, providing additional evidence for GPCR involvement.

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Describe the characteristics of CB1 and CB2 receptors

Both are GPCR
CB2 has been cloned
CB1 is primarily of interest [involvement in effects of the brain]
CB2 involve din periphery n immune systems
- CB2 receptors inhibit adenyl cyclase activity

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Describe the distribution of CB1 and CB2 receptors

CB1 Receptors:
- Expressed in various brain regions:
  - Ventral Tegmental Area (VTA) and Locus Coeruleus (LC) involved in dopamine release and euphoria.
  - Hypothalamus for autonomic activity, appetite regulation, and homeostasis control.
  - Found in areas related to memory (hippocampus) and pain (Periaqueductal Gray - PAG).
CB2 Receptors: prominently expressed in immune cells.

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What are CB1’s signaling mechanisms?

CB1 receptors are coupled with calcium channels, modulating calcium currents [it is a GPCR]
Activates potassium channels → increased potassium currents.
Inhibition of Protein Kinase A (PKA), influencing cAMP responses.
Direct effects on vesicle release and neurotransmitter release.

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What are CB1’s regulatory mechanisms?

Beta-Arrestin:

Involved in internalizing CB1 receptors.
Contributes to the desensitization of CB1 receptor activity.

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Describe the physiological effects observed in mice with CB1 receptor knockout.

Don’t live as long (significantly reduced in KO mice)
Lose weight
- Resistant to obesity
- Enhanced leptin sensitivity
  - Leptin is a hormone that tells you you’re full
Loss of THC induced hypothermia
Less pain sensitive in some tests of supraspinal pain responses
- No change in hypothermia
- Increase in catalepsy
- Analgesia assays
  - Tail flick = how quickly it flicks
  - Hotplate assay
  - Formalin
    - Reduced response
CB1 receptor itself is pro-analgesic
- Induce less pain when KO

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What are the endogenous ligands that bind to cannabinoid receptors?

Anandamide: endogenous lipid that can stimulate cannabinoid receptor-mediated signal transduction.
2-AG (2-Arachidonoylglycerol):
- Derived from the canine gut.
- Demonstrated in vivo effects similar to THC.
Other Endogenous Cannabinoids:
- Various other endogenous cannabinoids have been discovered.

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How is anandamide produced and released?

Production on Demand:
- Anandamide is not stored in vesicles like classical neurotransmitters.
Calcium-Sensitive Enzymes:
- Produced following the elevation of intracellular [Ca2+].
- Enzymes involved, such as N-acyl-phosphatidylethanolamine specific phospholipase D (NAPE-PLD), are calcium-sensitive.
Source:
- Anandamide is obtained from the enzymatic hydrolysis of N-arachidonoyl-phosphatidylethanolamines (NArPE), a membrane phospholipids.

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What is the production mechanism of 2-AG?

Produced on demand
- Derived from sn-1-acyl-2-arachidonoylglycerols (DAGs) in the cell membrane
- Acts as a neurotransmitter
Calcium-Sensitive Enzymes:
- Production involves calcium-sensitive enzymes.
- sn-2-selective DAG lipases (DAGLs), specifically DAGL-α and DAGL-β, catalyze the conversion of DAGs into 2-AG.

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How are cannabinoids synthesized and released?

Production from Phospholipids:
- Endocannabinoids (e.g., anandamide, 2-AG) are produced from phospholipids in the cell membrane.
- Cleavage of phospholipids occurs when intracellular [Ca2+] increases.
On-Demand Production:
- Production of diacylglycerol (DAG) and subsequently 2-arachidonoylglycerol (2-AG) is calcium-dependent.
- These lipids are not stored but produced on demand.
Receptor Activation:
- Released endocannabinoids can activate receptors present in both post and presynaptic neurons.
- Cannabinoids can act in a normal or retrograde (backwards) fashion.
Enzymatic Breakdown:
- Once released, endocannabinoids are broken down by enzymes.
- Main enzymes involved: Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH).
Presence in Glial Cells:
- Endocannabinoid receptors are also present in glial cells.
Transporter Involvement:
- Endocannabinoids may be released from cells through transporters like the endocannabinoid membrane transporter (EMT).

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What is the role of FAAH (Fatty Acid Amide Hydrolase) in relation to anandamide and analgesia?

Main metabolizing enzyme for FAA which include anandamide
If KO, mice hv analgesic phenotype
- Less pain in response to hot plate n tail flicking
FAAH KO mice display super-sensitivity o exogenous anandamide
- Bigger drop in temperature

What is the role of FABP5 as a cannabinoid transporter, and how does it impact endocannabinoid signaling?

Functional Impact:
- Pharmacological inhibition or genetic deletion of FABP5 abolishes phasic and tonic endocannabinoid (eCB)-mediated control of excitatory synaptic transmission.
- FABP5 appears to play a crucial role in the transport of lipids involved in endocannabinoid signaling.
KO Impact → loss of cannabinoid signaling.
On-Demand Cannabinoid Production:
- Unlike traditional neurotransmitters stored in vesicles, cannabinoids are produced on-demand.
- Cannabinoids, released by Endocannabinoid Membrane Transporter (EMT), activate FABP5.
- This unique signaling mechanism allows for transfer from postsynaptic to presynaptic neurons and vice versa.

What is Depolarization Suppression of Inhibition (DSI), and how is it related to endocannabinoid signaling?

DSI: depolarization of a principal neuron results in the suppression of inhibitory signals (IPSPs).
GABA: neurotransmitter associated with IPSPs
APs in interneurons depolarize the principal cell for a brief period.
- Following depolarization, IPSPs become smaller and less frequent, indicating reduced inhibition.
- During depolarization, Ca channels open → increase in intracellular Ca levels → endocannabinoids production
  - Endocannabinoids are released and act on CB1 receptors to inhibit the release of GABA from interneurons.
When the experiment is repeated with a CB1 receptor antagonist, no significant changes occur.
Application of Win55, a compound that mimics the effects of cannabinoids, replicates the observed reduction in IPSPs.

How do cannabinoids impact glial cells, and what role do glial cells play in the endocannabinoid system?

Cannabinoids can activate glial cells in addition to neurons.
Glial cells, particularly astrocytes, respond to cannabinoid signaling.
Astrocytes hv CB1R, allowing them to be influenced by cannabinoids.
- CB1R activation in astrocytes → physiological effects, such as blood vessel dilation (bloodshot eyes).
Cannabinoid-induced activation of astrocytes can impact blood vessels, leading to effects like bloodshot eyes.
Elevated calcium levels in glial cells may contribute to these vascular changes.
Glial cells, when activated, have the capability to release neurotransmitters, including ATP
Cannabinoid-activated glial cells releasing neurotransmitters can influence synapses and alter the overall neurotransmission.
This interaction highlights the broader modulatory role of cannabinoids in both neuronal and glial cell communication.

What are synthetic cannabinoids, and what are some key characteristics associated with their use?

Synthetic chemicals either sprayed on dried, shredded plant material so they can be smoked or sold as liquids to be vaporized and inhaled in e-cigarettes and other devices (liquid incense).
Not for human consumption: labels often claim that they contain “natural” material taken from a variety of plants.
Not easily detectable in urine and blood samples

Effects of synthetic cannabinoids

Higher prevalence of severe adverse effects
- Hypertension, tachycardia, hallucinations, agitation, seizures, and panic attacks that often require immediate medical care

How is Nabilone used in managing nausea and vomiting associated with cancer chemotherapy?

Medical Use:
- Condition: Nausea and vomiting related to cancer chemotherapy.
- Prescription: Nabilone is prescribed in the UK for patients unresponsive to conventional anti-emetics.
Effectiveness:
- Study: A systemic review involving 1366 patients compared oral nabilone and dronabinol.
- Outcome: Found to be significantly more effective than standard anti-emetics (BMJ 323 16-21).
Desirable Side Effects:
- Positive Effects: Sedation, drowsiness, and euphoria are reported as desirable side effects.
Undesirable Side Effects:
- Adverse Effects: Some undesirable side effects include dizziness, dysphoria, depression, hallucinations, paranoia, and hypotension.
- Consideration: Balancing the positive and negative effects is essential in determining the overall suitability of Nabilone for individual patients.

Where are CB1 receptors concentrated?

Areas that modulate nociceptive processing (opioid receptors)
Nociceptive = pain

What types of analgesic actions are exerted by CB1 and CB2 receptor agonists?

CB1: central n peripheral analgesic
CB2: peripheral analgesic
Dual mechanism suggests a potential comprehensive pain modulation.

What have some recent studies shown regarding cannabinoids and cancer pain?

- Few human studies on the topic. - However, recent studies on cancer pain have shown encouraging results.

What is the relationship between cannabinoids and appetite stimulation in the context of cancer-related issues?

- Cannabinoids are explored for addressing problems such as anorexia, early satiety, weight loss, and cachexia in cancer patients. - Stimulatory effect on appetite suggests potential benefits in managing these cancer-related complications. - Many animal studies demonstrate that THC and other cannabinoids have a stimulatory effect on food intake and appetite. - 2 small trials have shown that oral THC stimulates appetite and may slow down weight loss in patients with advanced malignancies.

What is Sativex, and what does NICE recommend regarding its use in MS?

- Sativex is an oromucosal spray containing THC, CBD, and other components derived from the cannabis sativa plant. - NICE recommended against using Sativex for treating spasticity in MS, citing it as not a cost-effective treatment.

What positive effects have been observed in clinical trials involving cannabinoids for multiple sclerosis (MS)?

- Clinical trials suggest positive effects of cannabis, Δ9-THC, or other CB receptor agonists on symptoms like spasticity, spasms, and pain in MS. - **Meta-Analysis Findings:** reduction in motor dysfunction and pain associated with MS. - Increased incidence of non-serious side effects has been reported in these studies.

What evidence exists regarding the impact of THC on tumor growth?

- Cell cultures and animal models suggesting that THC inhibits the growth of some tumors. - Studies on mice and rats propose that certain cannabinoids, including THC, may have a protective effect against tumor development.

Reported benefits of CBD

- Relieve pain - Treat depression and anxiety - Alleviate cancer-related symptoms - Reduce acne - Neuroprotective properties - Increase cardiac health - Other reported effects include: - **Antipsychotic effects:** help people with schizophrenia and other mental disorders - **Substance abuse treatment:** CBD has been shown to modify circuits in the brain related to drug addiction. - **Anti-tumor effects:** In test-tube and animal studies, CBD has demonstrated anti-tumor effects. significantly reduced inflammation - Anti-diabetic actions

What is the mechanism of action of CBD?

- Thought to inhibit the uptake of anandamide (endocannabinoid) → leading to increased levels in the body - Activates TRPV1 receptors, which play a role in pain perception. - Activate GPR55 receptors, considered a potential new cannabinoid receptor (orphan receptor). - CBD has been associated with the activation of 5-HT1A receptors (found in the hypothalamus and cortical areas) - CBD is suggested to modify the uptake of adenosine, a neurotransmitter with various physiological roles.

What are some side effects and long term risks of CBD?

- temporary hallucinations - temporary *paranoia*—extreme and unreasonable distrust of others - worsening symptoms in patients with *schizophrenia* - linked to other mental health problems, such as depression, anxiety, and suicidal thoughts among teens. However, study findings have been mixed.