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Welcome to the Deep Dive.
Today, we're diving into, well, a really complex topic,
cannabis pharmacotherapeutics, specifically for pain management.
Right, we want to extract the most critical info for advanced practice students.
Think mechanisms, indications,
safety.
Exactly.
Our mission is to pull out that high -yield knowledge you absolutely need.
And cannabis, I mean, it's been used for thousands of years, over 12 ,000 actually, but it's tricky, it can be good, it can be bad.
We're not doing the whole history lesson though.
No, no, we're focused squarely on the science, how the chemicals in the plant interact with our bodies, especially with pain systems.
Okay, so let's set the stage.
We need to get our heads around the body's own system.
First, the endocannabinoid system, or ECS.
Definitely.
And then look at the actual compounds from the plant, like THC and CBD.
And importantly, the FDA -approved drugs you might actually prescribe, plus how to use them safely.
Let's start with the plant itself.
Clinically, what matters most.
It's really about the flowers on the female plant.
They have these resin glands, right, the bracts, and they produce this sticky stuff, the tag combs.
And that's where the good stuff is, the cannabinoids, like THC and CBD, and also terpenes.
Terpenes give it the smell, right.
Right.
But we'll come back to those.
Let's focus on the big two cannabinoids.
Yeah, over 100 cannabinoids exist, but clinically, it boils down to THC tetrahydrocannabinol, which causes the high.
The psychoactive effects.
Correct.
And CBD cannabidiol, which doesn't have that psychoactive effect, but has shown other benefits, like analgesic and anti -inflammatory properties.
And there are different plant types too.
Sativa versus indica.
Generally speaking, yes.
Cannabis sativa tends to have higher THC relative to CBD.
Cannabis indica often has more CBD compared to THC.
But honestly, modern cultivation makes these distinctions a bit blurry sometimes.
Okay, so these plant chemicals interact with our own internal system, the ECS.
This was only discovered relatively recently, right?
Early 90s.
That's right, and it's a fundamental regulatory system.
Think of it like a master control panel for maintaining balance or homeostasis.
Balance in what areas?
Key areas like pain perception, appetite regulation,
immune function, mood,
memory.
It's quite widespread.
And the way it works is unusual.
You mentioned something about it working backwards,
retrograde signaling.
Yes, that's a crucial point.
Most nerve signals go one way.
Presynaptic neuron sends a signal, postsynaptic neuron receives it.
Standard stuff.
But the ECS uses its own messengers called endocannabinoids, things like anandamide and 2 -AG.
These are libids, fats, basically.
And they're made in the receiving neuron, the postsynaptic one, on demand.
So made only when needed.
Exactly.
And then they travel backwards across the synapse to receptors on the sending neuron, the presynaptic one.
So the receiving cell tells the sending cell to what?
Calm down.
Precisely, it's a feedback mechanism.
It tells the presynaptic neuron to slow or stop releasing its neurotransmitter, whether that's glutamate, GABA, or something else.
It fine -tunes the signal locally.
Fascinating.
And the receptors these endocannabinoids bind to are CB1 and CB2.
Those are the two main ones we talk about.
CB1 receptors are found mostly in the central nervous system, brain and spinal cord.
Makes sense for effects like pain perception, memory, mood.
Exactly.
And CB2 receptors are primarily found outside the CNS in the periphery, especially on immune cells.
So related more to inflammation and immune responses.
That's the general thinking, yes.
Now, how do THC and CBD fit in?
Right, back to the plant compounds.
THC acts as a partial agonist at both CB1 and CB2.
It sort of mimics our own endocannabinoids, but maybe not perfectly.
So it directly activates these receptors?
Yes, and activating CB1 in the brain is what leads to many of its effects, including the psychoactive ones, and also its potential therapeutic effects by reducing neurotransmitter release.
Okay, and CBD?
CBD is quite different.
It has a very low affinity for CB1 and CB2.
It doesn't really bind to them strongly.
So it doesn't activate them like THC?
Not directly.
In fact, it might even act as an antagonist, blocking them slightly or modulate them in other ways.
It seems to influence the ECS more indirectly, perhaps by affecting the enzymes that break down our own endocannabinoids or interacting with other receptor systems entirely.
So less direct pushing, more modulating.
That's a good way to put it.
And critically, without causing that THC -like high.
Okay, that clarifies the basic mechanism.
Let's pivot to clinical use.
What's the solid evidence say?
You mentioned Nessim 2017.
Yes, the National Academy's report is a key reference.
They found substantial or conclusive evidence for cannabis or cannabinoids in three main areas.
What are they?
First, chronic pain in adults.
We're talking neuropathic pain, fibromyalgia, rheumatoid arthritis pain.
Okay, chronic pain, number two.
Chemotherapy -induced nausea and vomiting, CINV.
A classic use.
And third.
Spasticity symptoms related to multiple sclerosis MS phenoja.
So chronic pain, CINV, and MS spasticity.
That's where the strongest evidence lies.
According to that major review, yes.
They also found moderate evidence for helping with short -term sleep problems, but usually linked to those same chronic conditions.
Got it.
But using cannabis medically isn't straightforward because of the legal situation, right?
Absolutely.
Federally, marijuana is still schedule one.
That means high abuse potential, no accepted medical use in the eyes of the federal government.
Which creates a real conflict with state laws and clinical practice.
It does.
The big change recently was the 2018 Farm Bill.
This is important for you to understand.
What did that do?
It legally separated hemp from marijuana.
Hemp was defined as cannabis sativa, containing less than 0 .3 % THC by dry weight.
So very low THC.
Right.
And the bill made hemp and derivatives like CBD from hemp federally legal.
Anything over 0 .3 % THC is still marijuana, still scheduled federally.
Okay, so that's why we suddenly saw CBD products everywhere.
Exactly, the market just exploded.
But this leads to a huge clinical pearl.
Which is?
These over -the -counter CBD products are largely unregulated.
Studies have shown really poor quality control.
Like?
Like inaccurate labeling.
One study found something like 43 % of products tested had significantly less CBD than the label claimed.
Some even had undisclosed THC.
Wow, so you can't trust the label.
Pretty much.
So you must ask your patients if they're using any OTC CBD products.
Because what they think they're taking might be very different from reality.
Okay, crucial point.
Since whole plant marijuana is federally tricky, let's focus on the FDA approved options.
The ones you can actually prescribe legally.
Right.
There are three main ones covered in the source material.
And for all of them, the starting principle is universal in pharmacology.
Let me guess.
Start low, go slow.
You got it.
Especially with cannabinoids due to the potential for CNS effects.
So what are the three?
Okay, first we have Dronabinol.
Brand names are Marinol and Syndros.
This is synthetic THC.
Synthetic THC.
What's it approved for?
Two main things.
CINV, chemotherapy nausea vomiting, and appetite stimulation for anorexia associated with weight loss in AIDS patients.
Dosing for CINV.
It's based on body surface area.
Starting around five millimeters for Marinol, or 4 .2 millimeters for Syndros, given one to three hours before chemo.
Are Marinol and Syndros interchangeable?
Not exactly, and this is critical.
Marinol capsules contain sesame oil.
Big contraindication if your patient has a sesame allergy.
Don't crush or chew them either.
Okay, sesame oil for Marinol.
What about Syndros?
Syndros is an oral solution, and it contains 50 % dehydrated alcohol.
This is a massive red flag.
Why?
Drug interactions.
Huge ones.
You absolutely cannot give Syndros to patients taking Desulfuram, Antabuse,
or Metronidazole, flagell.
The alcohol load can cause a severe, potentially life -threatening Desulfuram -like reaction.
Nausea, vomiting, flushing, palpitations, bad news.
Very bad news.
You have to screen for this interaction diligently.
It's not a minor warning.
Got it.
And side effects for Geroniminal generally, since it's synthetic THC.
Pretty much what you'd expect from THC.
Yeah.
Dizziness, feeling high or euphoric.
Sleepiness, sometimes paranoia or abnormal thinking.
Nausea can actually be a side effect too, ironically.
And the warning about driving or operating a machinery is essential.
Non -negotiable, they are impaired.
Okay, that's Geroniminal.
What's the second one?
Navalony, brand name Sesame.
It's also a synthetic cannabinoid, similar to THC.
Another THC -like drug.
Indication.
Also CINV, specifically for patients who haven't responded well to standard anti -nausea meds.
How's the dosing?
Usually starts at one or two milligrams twice a day.
Can go up to six milligram total per day if needed.
Again, start low.
Key cautions or contraindications for Navalony?
Besides hypersensitivity, the big one is cardiac conditions.
It can cause tachycardia, palpitations and orthostatic hypotension dizziness when standing up.
Use very cautiously there.
Anything else?
Yes, psychiatric conditions.
Avoid it if possible in patients with a history of psychosis, like schizophrenia or bipolar disorder, as it could potentially worsen symptoms.
Makes sense, given the THC -like effects.
Okay, so two synthetic THC options.
What's the third FDA -approved agent?
The third one is different.
It's Cannabidiol, brand name of Pediolex.
This is purified plant -derived CBD.
Ah, so actual CBD from the plant, but purified and FDA -approved.
Correct.
Its mechanism is thought to involve analgesic, anti -inflammatory and anti -convulsant effects, but without the psychoactive high of THC.
As we said, low affinity for CB1, CB2.
And what's the specific FDA -approved indication for a Pediolex?
It's quite narrow, isn't it?
Very narrow.
It's approved only for seizures associated with two specific severe childhood epilepsy conditions.
Lennox -Gastaut syndrome, LGS, and Dravet syndrome, DS, in patients aged two years and older.
So not for pain, not for CINV, specifically these seizure disorders.
That's its current FDA approval, yes.
Dosing is weight -based, starting at 2 .5 milligrams twice daily, potentially increasing, requires dose adjustment for liver impairment.
And that brings us to the major safety concern with a Pediolex, right?
The liver.
Absolutely critical point.
A Pediolex carries a significant risk of hepatocellular injury.
You can see elevated liver enzymes, ALT and AST.
When does this usually happen?
Typically within the first couple of months of starting therapy.
Monitoring liver function tests is mandatory.
And what's the threshold for stopping the drug?
If the transaminase levels go above three times the upper limit of normal, especially if bilirubin also increases, treatment must be discontinued.
This is a serious potential side effect.
Okay, hepatic monitoring is key for a Pediolex.
Common side effects otherwise.
Mostly things like drowsiness, sedation, fatigue, decreased appetite, and some GI issues like diarrhea.
So to recap the three FDA drugs,
dronal banal, synthetic THC, CIN vanorexia, watch susum alcohol.
Nibelone, synthetic THC, CINV, watch cardiac site.
A Pediolex, plant CBD seizures, watch liver.
That's a good summary.
Always start low, go slow.
Now let's think about clinical application and monitoring.
The overall goal is?
Reduce pain to a tolerable level, improve function, improve quality of life.
Practical goals.
Let's use that case study example.
A 67 -year -old with chronic neuropathic pain is on dronal banal.
They're also taking Atenolol, Symbostatin, and Tramadol.
What jumps out?
The Tramadol immediately.
Both dronal banal, THC, and Tramadol can cause CNS depression, dizziness, sedation, confusion.
An additive effect, a pharmacodynamic interaction.
Exactly, you've got two drugs hitting the CNS in similar ways, increasing the risk of side effects.
So if that patient reports feeling confused, maybe having dry mouth, or ataxia difficulty with coordination, what's the first step?
First, consider lowering the dronal banal dose.
Maybe try 2 .5 milligram, BID, or even just once daily.
See if the side effects improve.
But you also need to investigate further, right?
Absolutely, you need to ask, are they using any other cannabis products?
Smoking marijuana on the side, that would add to the total THC load.
Or other CNS depressants, alcohol, benzodiazepines.
Right, you need the full picture before just adjusting the prescribed dose.
Rule out confounding factor.
Good point.
What about specific populations?
We mentioned a Kidiolex for kids two and up with liver monitoring.
How about older adults?
Geriatrics use all cannabinoids very cautiously.
The sedative effects increase the risk of falls and cognitive impairment.
Always start at the lowest possible dose and monitor very closely.
And pregnancy?
The recommendation is strong.
Avoid use during pregnancy and breastfeeding.
There's limited data, but some potential risks, like lower infant birth weight have been suggested.
Better to err on the side of caution.
Okay, let's wrap up with patient education.
What are the absolute must -tell points?
Patients need to understand cannabis affects many systems.
It can reduce anxiety, cause sedation, help pain, common side effects,
dizziness, dry mouth, sleepiness, maybe altered time perception.
And the THC component specifically.
But DAC -HI involves perceptual changes, impaired thinking and coordination.
It's similar to alcohol in its impairing effects.
So the message about driving is?
Absolutely critical.
Never ever operate a vehicle or heavy machinery while under the influence of any cannabinoid product, prescribed or otherwise, impairment is real.
Okay, let's quickly recap the core takeaways.
Remember the ECS, that unique retrograde feedback system.
Understand the key difference.
THC is a direct agonist, pushing the system, causing psychoactive effects.
CBD has low affinity, modulates more indirectly, no high.
And for the FDA approved drugs.
Vigilance, dronabinol, watch for sesame allergy, marinal and alcohol interactions.
Syndros, nabolone, caution with cardiac and psych history,
Epidiolex, mandatory liver monitoring, start low, go slow for all.
Excellent summary.
Now for that final thought to leave our listeners with, building on the material, we mentioned terpenes earlier.
Ah yes, the volatile compounds that give cannabis its distinct smell like pine, citrus, mint.
Things like limon or pine or mercine, they aren't just smells, are they?
No, they appear to be pharmacologically active themselves.
And this leads to a really interesting concept called the entourage effect.
The entourage effect, what's the theory?
The idea is that the various compounds in the whole cannabis plant, THC, CBD, other minor cannabinoids, and either terpenes, work together synergistically.
The overall effect is greater or perhaps different than some of its parts.
So an isolated synthetic THC like dronabinol might not capture the full therapeutic potential that a whole plant extract with its natural blend of cannabinoids and terpenes could offer.
That's the hypothesis.
It suggests that maybe focusing only on isolated molecules misses something important about how this plant works therapeutically.
So a provocative question for you, our listener, as you go into practice.
Could future drug development move beyond single molecules?
Might we see FDA approved products designed with specific ratios of cannabinoids and terpenes to harness this entourage effect for better patient outcomes?
Something to think about.
Definitely food for thought.
Thank you for joining us for this deep dive into the complex world of cannabis pharmacotherapeutics.