THC and gabapentin interactions in a mouse neuropathic pain model
Add to Mendeley
We examined interactions between tetrahydrocannabiniol (THC) and gabapentin in a mouse neuropathic pain model.
THC and gabapentin synergistically reduced allodynia.
Coadministration with gabapentin increased the therapeutic window of THC.
Thus, THC may provide an adjuvant to current neuropathic pain medications.
Clinical studies have shown that the major psychoactive ingredient of Cannabis sativa Δ9-tetrahydrocannabinol (THC) has some analgesic efficacy in neuropathic pain states. However, THC has a significant side effect profile. We examined whether the profile of THC could be improved by co-administering it with the first-line neuropathic pain medication gabapentin. This was done using the chronic constriction injury (CCI) model of neuropathic pain in C57BL6 mice. At 8 days post-CCI nerve injury, acute systemic administration of gabapentin produced a dose-dependent decrease in CCI-induced mechanical and cold allodynia, and increased motor incoordination. Coadministration of THC and gabapentin in a fixed-ratio dose-dependently reduced mechanical and cold allodynia, and produced all the side-effects observed for THC, including motor incoordination, catalepsy and sedation. Isobolographic analysis indicated that the ED50 for the THC:gabapentin induced reduction in allodynia was 1.7 times less than that predicted for an additive interaction. The therapeutic window of combination THC:gabapentin was greater than that for THC alone. These findings indicate that gabapentin synergistically enhances the anti-allodynic actions of THC and improves its therapeutic window. Thus, THC may represent a potential adjuvant for neuropathic pain medications such as gabapentin.
Previous article in issue
Next article in issue
THC and gabapentin interactions in a mouse neuropathic pain model Add to Mendeley Highlights We examined interactions between tetrahydrocannabiniol (THC) and gabapentin in a mouse
CBD versus Gabapentin or Pregabalin – Research on Replacement, Withdrawals, and More
We’re used to inquiries (usually frantic) from people who are coming off of benzos like Valium, Xanax, and Ativan.
We covered how CBD works there in detail at our CBD versus Benzos or Using CBD to get off benzos her
Interestingly, we see about the same number of inquiries with Gabapentin.
What’s going on there?
Why has there been a big uptick in illegal sales of gabapentin?
It’s not good when your street name is “johnnies”.
Gabapentin is given out pretty freely as many doctors consider it safe and benign.
The usual suspects are sleep and anxiety (same as benzos) even though it’s officially an anti-seizure and neuropathic pain drug.
What users quickly find out is the brain’s trick called normalization.
It’s a nasty show and we’ll get into why it happens below.
More importantly, what does research show for CBD’s shared pathway for Gabapentin, and maybe more pressing is can it be used to replace or wean off Gabapentin?
Let’s get into it.
We’ll cover these areas:
- How do Gabapentin and Pregabalin work?
- Is Gabapentin an amino acid in sheep’s clothing?
- Gabapentin and the Serotonin effect
- CBD versus Gabapentin for GABA
- Side effect and safety comparison of CBD and Gabapentin
- Can you take Gabapentin and CBD together
- Can CBD help with Gabapentin withdrawal
Let’s get started.
How does Gabapentin work
We’ll focus on gabapentin but this information is similar for gabapentinoids like pregabalin (Lyrica) and gabapentin (Neurontin) alike. They do have a different profile in terms of addiction which we’ll discuss below.
First, let’s dig into how gabapentin works.
How it really works!
One note. most people know gabapentin by its brand name, Neurontin. Lyrica is a slightly different chemical although in the same gabapentin family.
Chemically, gabapentin is basically a synthetic version of GABA.
GABA is a naturally-occurring neurotransmitter in the brain that acts as a brake pedal.
In fact, it’s the most prominent of all our neurotransmitters and is tasked with the delicate balance across multiple pathways of calming down activity.
The opposing force is generally glutamate (gas pedal).
Consequently, with more GABA, we generally feel calmer or sleepier.
At the moderate level, lack of GABA can be anxiety or insomnia.
On the severe side, it can be seizures and nerve damage/death.
That’s the surface level effect of GABA that we feel but it’s much more complicated as you drill down into all the other neurotransmitters.
For example, gabapentin is used for neuropathic pain.
Why would boosting our brake pedal affect pain?
There’s research that points to hyperexcitability in nerves as being a key cause of neuropathy.
The level of glutamate is elevated in the spinal cord of rats during inflammation (Dmitrieva et al. 2004; Pitcher et al. 2007) and following nerve injury in neuropathic pain.
The body can get stuck in this hyperactive nerve state and result in actual nerve damage.
GABA is the firehose for this pain and inflammation fire.
We’ve discussed how benzos work (see CBD and GABA) by nudging the GABA receptors so they stay open longer or more easily.
The brain pushes back by suppressing GABA function as a knee-jerk reaction.
Hence, withdrawals, addiction, and tolerance.
Despite its name and even similarity to GABA, gabapentin works in a different way.
There are two main (for now) means of action:
- Boosting GAD conversion of glutamate to GABA
- Directly calming neuron activity via calcium channels
The best research shows that gabapentin plays at the point where GABA is made upstream from Glutamate (its opposition) of all things:
Gabapentin stimulates GAD at drug concentrations of 1.0 to 2.5 mM (Silverman et al, 1991; Taylor et al, 1992) and inhibits the GABA-catabolizing enzyme, GABA-transaminase (GABA-T) at high concentrations (23-25 mM; Taylor et al, 1992)
GAD is the enzyme that converts glutamate (gas pedal) to GABA (brake pedal).
The net effect:
gabapentin administration was associated with an average increase in GABA concentration of 55.7%
It appears to also bind directly to neurons and flip the electric charge (just like GABA does) so that activity calms down.
This is why you can actually have overdoses on Gabapentin.
In fact, on the Neurontin website:
Acute oral overdoses of NEURONTIN up to 49 grams have been reported.
The bigger overdose issue is with the black market use where people will use gabapentin to spike opioid use to exaggerate the high.
It’s still not understood why this happens.
Now, let’s shed a light on the more fascinating piece.
Is Gabapentin an amino acid in sheep’s clothing?
So, it’s not GABA as most people (and doctors) think.
As we mentioned, their primary effect may be by affecting those calcium channels (see CBD and GABA function to understand the whole electric thing).
Guess what else has a very similar liking for these channels.
L-Leucine and L-Isoluecine!
Two important amino acids.
This partially explains why gabapentin and pregabalin (Lyrica) interact at the level they do. they’re competing with the natural players. L-leucine and L-Isoleucine for these same pathways!
Let’s test it.
Let’s look at situations of hyperexcitability that GABA would normally help with.
We’ll start with seizures.
Unexpectedly, the D-enantiomer of leucine, which is found in trace amounts in the brain, worked as well or better than L-leucine against both kainic acid and 6 Hz electroshock-induced seizures.
Here’s the kicker…
D-leucine suppressed ongoing seizures at least as effectively as diazepam but without sedative effects.
Remember how we said seizures were at the severe end of the pool with an imbalance for excitability pathways.
What about insomnia or anxiety? Or Neuralgia?
Preclinical evidence strongly suggests that dietary BCAA supplementation restores normal sleep-wake patterns and cognitive function following TBI through a restoration in the global cortical excitation: inhibition ratio.
BCAA are the amino acids we can’t make ourselves – leucine, isoleucine, and valine.
Interestingly, they are responsible for more than 50% of the glutamate and GABA production!
It all dovetails back around.
What about anxiety and mood imbalances?
The BCAAs are significantly decreased in patients with major depression in comparison with healthy subjects (valine: Mann-Whitney-U: 968.0; p What about a genetic issue where leucine is not functioning correctly?
Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities
Okay. we’ll have to do a deeper dive on leucine and the BCAA cohort.
By the way, leucine is a key driver of the whole keto movement. We’ll save that for further investigation.
One note. we take collagen peptides (Vital brands is a good one) to get all the amino acids aside from tryptophan. It’s in a ratio our bodies are designed to receive from a few 100 thousand years of eating skin, bones, and sinew.
Evolution can’t keep up with meatless burgers (or discount leucine!)!
Let’s look at another important neurotransmitter affected by gabapentin directly.
One, we know well from our studies on CBD and anxiety.
Gabapentin and the Serotonin effect
Serotonin is a master regulator in every aspect of human behavior.
That sounds like hyperbole but check out our CBD and serotonin review for more clarity.
- Appetite-suppressant? Check (see CBD and hunger)
- Can it delay orgasm? Check (see Can CBD make me last longer)
- Will it cause to reject unfair offers??
Yes. It’s that strange.
What’s the connection with gabapentin (neurontin)?
6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions.
Interestingly, it reduces other neurotransmitters which troubling.
Our first clue of the serotonin effect was the lst of side effects from Neurontin….especially the more severe ones.
They were specifically reminiscent of SSRIs and the lovely serotonin syndrome.
- Suicidal thoughts (see CBD versus SSRI for suicidal thoughts)
- Jerky or excessive body movements
- Inability to reach orgasm
Very reminiscent of serotonin syndrome (too much serotonin).
It also explains why it’s so hard to get off of gabapentin.
Officially, they call it serotonin discontinuation syndrome (Orwell would be so proud) but withdrawal is the more common vernacular.
We’ll look at Gabapentin withdrawal below but serotonin is probably a major part of that process.
Let’s finally get to the heart of this article. CBD versus Gabapentin.
CBD versus Gabapentin for GABA
Just a recap. gabapentin has been shown to:
- Increase glutamate to GABA conversion (via GAD enzyme)
- Binds to calcium channels (similar to leucine) to calm neuron activity
- Increases serotonin
- Decreases other neurotransmitters
- Suppresses glutamate receptor activity
A quick introduction is in order.
CBD is a cannabinoid naturally found in cannabis.
Most people know its cousin, THC, which has almost opposing effects in the body (see CBD versus THC here).
CBD works to support a key system we all have called the endocannabinoid system.
This system is tasked with balancing other key systems:
- Immune system – inflammatory agents
- Endocrine system – hormones
- Nervous system – including neurotransmitters like serotonin, GABA, and Glutamate!
That last one is critical for our discussion versus gabapentin.
Let’s look at the following:
- CBD and GABA versus gabapentin
- CBD and Serotonin versus gabapentin
- CBD for anxiety
- CBD for sleep
- CBD for neuralgia
First. the most obvious target. GABA.
Does CBD have an effect on GABA activity?
We’ve covered it in detail at our CBD and GABA review but some key takeaways.
First, researchers zeroed in on exactly what CBD did for GABA function:
CBD and 2-AG were positive allosteric modulators at α1-6βγ2 receptors, with low micromolar potencies.
2-AG is our most prominent endocannabinoid (naturally occurring) in the brain.
Basically, what they are saying is that CBD directly stimulates (when low) GABA function.
The Klingon looking word, α1-6βγ2, is a type of GABA receptor.
The modulator part is important.
We don’t want to just keep juicing GABA like benzos or even worse, barbituates.
That leads to the sedation and eventual overdose that occurs.
There isn’t a recorded overdose with CBD up to 1.5 grams.
The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site.
This is important as we looked at in our CBD and GABA function with a focus on the benzo activity there.
The first sentence in that study’s summary is telling:
Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties.
- Anti-anxiety (anxiolytic)
- Anti-hyperalgesic (reduces pain sensitivity)
Hmmmm….basically the main reasons many people are prescribed gabapentin.
What about the whole balancing act between GABA and glutamate?
One note. Gabapentin has been shown to suppress glutamate activity.
This partially speaks to some of its side effects (we’ll cover below).
Glutamate is important for focus, learning, motor control….basically anything that requires all systems firing.
It’s our gas pedal after all.
Gabapentin works in one direction. suppress glutamate. boost GABA-like function (leucine-esque).
What about CBD?
There are two interesting studies that point to supporting the balance of GABA/Glutamate function.
First, a study on schizophrenia (see CBD and schizophrenia).
A quick lay of the land.
When a baby is exposed to viral (see CBD and coronavirus) or bacteria infection during development, it can “prime” the immune system to overreact.
In schizophrenia, this can result in an imbalance between GABA and glutamate levels.
Researchers looked at this with CBD:
Overall, these findings show that CBD can restore cannabinoid/GABAergic signaling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure.
If you have a loved one affected by schizophrenia, make sure to read the review above as the studies are nothing short of breathtaking.
Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant.
Why on earth would it have a different result in the brains of people with autism?
This is so important to our discussion.
CBD’s effect appears to be based on the state of the system.
In people with autism, there can be too little activity (glutamate) in the prefrontal cortex. the part of our brain tied to planning, thinking, and most of the tasks that are difficult for people with autism.
CBD actually DECREASED GABA in that area but only in the people with autism!
Try to read that back over because although complicated, it’s so fascinating in terms of CBD’s true role.
Really, it speaks more to the power of the endocannabinoid system.
As for serotonin, we’ve covered that in-depth here:
This may be CBD’s greatest trick yet and the results are similar to GABA’s pathways above. Maybe even better.
Of course, we’re not trying to support or balance GABA just for the sake of.
Find out more on the net effects of this here:
Let’s turn to maybe the most important piece.
Side effect and safety comparison of CBD and Gabapentin
First, the list of gabapentin side effects courtesy of the Neurontin detail here:
The most common side effects are:
- Drowsiness (depending. see Can I take CBD in the middle of the day)
- Low blood pressure
- Dry mouth
A clarification. this assumes just CBD Isolate (CBD by itself).
Full-spectrum CBD can have a host of side effects as you see from our reviews with people who try full spectrum but run into issues (usually allergic or histamine – see CBD full spectrum versus Isolate here).
The bigger issue (for us after benzo and SSRI reviews) deals with normalization, addiction, and withdrawals.
Does CBD cause these effects?
First, an introduction (hopefully you’ll never meet).
Normalization (also called tolerance) is when the body/brain pushes back the other way from a given chemical.
With benzos, the brain will literally start to make fewer GABA receptors to offset the juicing of GABA levels by benzos.
This means you need more and more of the drug to have the same effect.
This also speaks to withdrawals.
For example, if you had anxiety before taking gabapentin, and the brain slowly ramps down natural GABA production, when the drug wears off, you’re in a worst situation than when you started.
In studies, CBD has not been shown to cause normalization or tolerance:
Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD.
What about addiction?
Addiction is many drugs that are usually carried out via our dopamine system.
Dopamine is a powerful neurotransmitter that partially governs the reward center.
It’s the “do that again” chemical.
Benzo’s, as an example, have been shown to boost dopamine and even prime their receptors for future benzo exposure. Very addictive.
The keyword there is “hedonic” or causing pleasure. That’s the main hammer of the reward process.
It’s the thing where lab mice will lever for nicotine instead of food or water.
What about CBD. is it hedonic?
CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement.
Not only is it not addictive, but it is also showing promise to help with other addictions (see CBD and addiction here).
This brings up to withdrawals.
Withdrawals are mainly due to the tolerance issue above.
You end worse than where you started and then the drug effects drop.
Again, not only does CBD not cause withdrawals, it’s getting recognition for helping with other withdrawals including one of the worst. opioids:
The study team found that CBD, in contrast to placebo, significantly reduced both the craving and anxiety induced by drug cues compared with neutral cues in the acute term.
This is the withdrawal piece of addiction.
Interestingly, they found the effects lasted for a period of time:
CBD also showed significant protracted effects on these measures seven days after the final short-term exposure.
It even affected heart rate and cortisol levels (which are usually elevated in an agitated state of withdrawal).
That’s CBD. What about Gabapentin?
This gets a little tricky because gabapentin has gained a street recognition for enhancing opioid highs and acting as a “come down” after using opioids.
It’s hard to separate the other addiction from gabapentin in the research.
There’s a good review of how gabapentin is abused here:
Interestingly, we found research on how gabapentin can release dopamine in the specific brain area usually tied to addiction. the nucleus accumbens:
intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats.
Other studies find euphoria as a result which would speak to our reward system:
Several case studies mentioned experiencing euphoria after gabapentin misuse that was reminiscent of, but not as strong as, opioids
This was usually in conjunction with another drug such as bupropion or opioids.
We need more research (pretty lacking in large scale) on gabapentin by itself.
- It’s generally abused in conjunction with another addictive drug
- Lyrica (pregabalin) appears to be more addictive than Neurontin (gabapentin)
- Some withdrawal and tolerance is noted in research – dose-dependent
A review of these associations are here:
This all brings up a good question that comes up regularly.
Can you take Gabapentin and CBD together
Many people investigate whether they can switch out CBD for gabapentin, primarily due to the side effect profile.
First, a quick word of warning.
Work with your doctor or naturopath for such any change with gabapentin as the effects can be significant if abruptly stopped.
It’s similar to benzos in that respect even with seizures as a result.
First, gabapentin is mainly cleared by the kidneys while CBD is metabolized by the liver.
CBD does not interact with the calcium channels mentioned above (shared by l-leucine) so they don’t appear to share that pathway.
The fact that CBD isn’t sedative or causing overdoses speaks to some limiting factor on how far it will push GABA (as opposed to gabapentin).
We just don’t have good research on the two together.
The general rule is to take CBD at least 4 hours away from other medications (work with your doctor).
As we discussed with our CBD and benzo withdrawals, our founder has a pill cutter and slowly sliced increasing slivers off of each pill over a 1 month period.
The research above shows that CBD helps to normalize GABA function but it was a slow process.
The max CBD dosage for neurogenesis (building new pathways – see CBD and neurogenesis here) is 300 mg per day.
I would take 150 mg in the morning and 150 mg before sleep.
The half-life of CBD is about 4-6 hours so it’s also possible to take one dose with each meal.
This amount should come down once the system balances.
A testing dose is usually 25-30 mg just to see how your body responds.
One note to ladies. estradiol and progesterone are powerful governors of both serotonin (estradiol) and GABA (progesterone).
We found this the hard way during a brutal perimenopause (that story is here).
This started in earnest mid-’40s and not addressing those two players (a common reason for gabapentin prescriptions) is likely not to lead anywhere.
See estradiol review or perimenopause review to understand why.
Most of the people we hear from are women in their 40’s and older. Go figure.
During the process of switching (use a good naturopath), we have to survive it. That’s next.
Can CBD help with Gabapentin withdrawal
There isn’t specific information on CBD and gabapentin but we do have gabapentin’s usual bedmate. opioids.
First, what are we looking at with gabapentin withdrawal?
Withdrawal symptoms, often resembling those of benzodiazepine withdrawal, play a role in the physical dependence some users experience.
Okay. that makes sense since both are working on the inhibitory system (calming neurons down).
This would result in anxiety, agitation, insomnia, etc. Classic withdrawal symptoms really.
Let’s look at research across a range of drugs and see how the addiction pathway can be very similar.
the administration of cannabidiol (CBD), a very promiscuous phytocannabinoid with at least a dozen mechanisms of action, also alleviates naloxone-precipitated withdrawal in morphine tolerant rats.
Then there’s are favorite….cannabis! THC really.
For the percentage of the population that can become addicted to cannabis (because of THC):
Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment.
Rebalancing of the GABA/glutamate and serotonin systems are key for withdrawal but what about the habitual nature of any misused drug.
As we mentioned above, CBD is now showing as a powerful agent to suppress the nasty effects of opioid withdrawals and the long term changes are what we find to be interesting.
For example with the opioid withdrawal study:
Intriguingly, CBD’s effects were prolonged, lasting two or more weeks after administration in its efficacy to reduce heroin reinstatement behavior triggered by drug-specific environmental cues.
The fact that this is long term really gets to the heart of what’s going on with CBD.
This is neurogenesis. The brain learning new tricks (or pathways at least).
Many addictions are starting to look like ruts or patterns that get locked in.
This speaks to why psilocybin (see psilocybin review) from magic mushrooms is so impressive for addiction.
The ability to upset the apple cart can be a powerful thing in the brain.
Also, consider l-leucine if coming off of gabapentin. Always with your naturopath!
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.
The response you had to full spectrum is exactly why we focus on CBD isolate. This is likely a histamine response to the plant material or bad product. We original ran through 3-4 of the biggest brands of CBD. Almost gave up on CBD altogether. Isolate has a completely different response and CBD itself is shown to calm histamine response (and inflammation in general) in research. You can search for any of the mentioned reviews at top of page.
We did big review on neurogenesis and CBD which is the key to how it works for depression, etc. The same effect is important for peripheral nerve pain. Also, check out NAC (review above in search) which calms glutamate activity. Glutamate drives nerve damage when excessive and NAC “soaks up” excess glutamate. Also, get your Vitamin D levels checked. So many people are deficient and we don’t mean the 30 level used for rickets. Endocrinologist want levels closer to 70-80 and if you have a VDR gene variant (like me), it can take 10K IU daily to get it to budge. Finally, you have check progesterone and estrogen levels. One promotes immune system restraint (source of glutamate) and balance while the other drives growth (serotonin from estrogen). So critical for nervous system. Your new best friend is BDNF…which estrogen drives! Sorry for all the detail…just lots of research. We looked at CBD and neuropathy for perimenopause here since that’s how we found CBD to begin with! Same pathways at play.
I have had face , nerve pain for 45 years , I have tried to avoid pharmaceutical drugs . I tried 3 brands of full spectrum CBD oil . I felt weak and sick to my stomach and lost my appetite . I felt it was my last resort . It doesn’t make since to me . Is there a organic good pure cbd ?
Learn about the shared pathways between CBD and these GABA pathways compounds. CBD versus Gabapentin or Pregabalin