How to Use CBD Oil For Pain Relief (Scientific Evidence, Effects, and Dosages Explained)
Today, you’re going to learn everything about how to use CBD oil for pain management.
We reviewed over 50 scientific articles that looked at:
- The potential benefits and effects of CBD, including for pain;
- The mechanisms of action that give CBD its painkilling properties, and;
- What doses of CBD were found effective in different studies for reducing pain.
The results we found are a MUST-read for anyone interested to explore the potential benefits of CBD oil for pain management.
You’re going to learn exactly what type of CBD oil has the most potential to give you pain-relieving effects.
What you need to do to maximize CBD oil’s potential for pain relief. Plus, you’re going to learn whether topical CBD products may be a better alternative or not.
Table of contents:
Summary of Main Points
- Although CBD oil may reduce pain, it’s not a cure for pain;
- CBD may reduce pain by interacting with opioid receptors, serotonin receptors, adenosine receptors, vanilloid receptors, and glycine receptors;
- CBD has been shown to reduce chronic pain in kidney transplant patients ;
- CBD has been shown to have an anti-inflammatory effect on intestinal inflammation ;
- Topically applied CBD has been shown to reduce arthritis-associated pain in rats;
- The kidney-transplant-study found CBD dosages ranging between 100mg and 300mg to be effective for reducing pain;
- Different studies indicate that the most potent way to use CBD is by using it in the form of a full-spectrum hemp-extract;
- When using a full-spectrum CBD oil, you might need a much lower dosage to experience CBD’s pain-reducing effects;
Below you can find a quick step-by-step summary on how to use CBD oil for pain. If you want to dive deeper into the science of using CBD for pain, please read the full article.
Ste-By-Step Summary of How to Use CBD Oil for Pain:
- Get a high-quality full-spectrum CBD oil (we highly recommend Receptra Naturals);
- Take your CBD oil within 2-hours after a meal that contains at least some healthy fats like olive oil;
- Drop a dose that equals 25mg of full-spectrum CBD under your tongue;
- Keep this dose under your tongue for 60 seconds;
- Swallow the dose of oil;
- Take a second dose at least 8-hours after you took your first dose. Taking CBD orally takes 2-4 hours before it reaches its maximum effect and then slowly the effects diminish;
- In case of no effects, slowly work your way up in 10mg increments until a maximum dose of 300mg of CBD;
- While generally, we don’t recommend taking orally consumed CBD more often than 1-time per 8 hours, in the case of pain management, based on the kidney-transplant-study, taking doses more frequently within an 8-hour time-span could prove to be useful;
- Take your CBD oil daily, for at least 15 days before judging its effectiveness.
The Types of Pain CBD May Relieve (Review of Studies)
While commercially produced and sold CBD oil is not a medicine, scientific research has shown that CBD, the main constituent of CBD oil, can have beneficial effects on pain-related conditions.
CBD and Chronic Pain
Various studies found beneficial effects of CBD for chronic pain.
However, most of these studies are done on animals.
For example, a study published in 2012 by the Journal of Experimental Medicine, looked at the effects of CBD on chronic inflammatory and neuropathic pain in mice (1).
They found that CBD significantly suppresses chronic inflammatory and neuropathic pain through interacting with glycine receptors, without building any tolerance levels or side effects.
Glycine receptors (GlyRs) play an important role in the regulation of pain at the spinal level.
One recent 2018 study done on human kidney transplant patients study that looked at the effects of CBD in chronic pain treatment (2) found that:
- 2 out of 7 patients had a total pain improvement with an initial dose of 100 mg of CBD/day and a progressive increase of up to 300 mg of CBD/day (spread out over the day in smaller doses);
- 4 out of 7 patients had a partial pain improvement with an initial dose of 100 mg of CBD/day and a progressive increase of up to 300 mg of CBD/day (spread out over the day in smaller doses). With these patients the pain lessened significantly but didn’t completely disappear, and;
- 1 patient didn’t improve at all.
Interestingly enough, this same study found that 1 patient experienced much better pain control with a lower dose of CBD (less than 300 mg of CBD/day). This means that more CBD is not always better!
CBD and Digestive Pain/Inflammatory Bowel Disease
There has been some research in regard to cannabinoids and improving gut health as well as relieving the pain associated with conditions like inflammatory bowel disease.
Researchers have found evidence, as suggested in “Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?” (3), that cannabinoids can have beneficial effects on inflammatory bowel diseases (IBDs).
Of all cannabinoids both THC and CBD have the biggest potential.
CBD is protective of intestinal inflammation.
Pre-clinical studies have shown that CBD has an anti-inflammatory effect on intestinal inflammation (4).
While the exact mechanism responsible for this effect needs further research, researchers have found at least some evidence that CBD acts as an antagonist to GPR55, a receptor that plays a crucial role in intestinal inflammation.
By binding to the GPR55 receptor, CBD could work as a desensitizing agent on this receptor, which might lead to a decrease in inflammation.
CBD and Arthritis Pain
Arthritis is characterized by inflammation of the joints.
Research published in 2016 in the “European Journal of Pain” found a dramatic reduction in inflammation and signs of pain (5), without adverse side effects in rats with arthritis after the animals were given a topical gel that contained CBD for four days.
It makes sense that CBD could help relieve any inflammation-related pain condition due to its powerful anti-inflammatory effects.
There are many users of CBD oil who have anecdotally reported that it helps to relieve not only pain but other inflammatory conditions as well, like: multiple sclerosis, nausea, PTSD, Alzheimer’s disease, insomnia, and epilepsy, in addition to all of the above though, studies are still needed to confirm these effects.
Note: CBD may not only relieve physical pain but mental pain like anxiety and depression as well.
CBD and Cancer-related Pain
Different studies have found that oromucosal sprays containing both CBD and THC, were effective in improving cancer-related pain.
For example, one study looked at the effects of a CBD- and THC-containing spray called Sativex on pain in patients that were diagnosed with pain related to terminal cancer and that was not fully relieved by strong opioid painkillers (6).
The study found that the CBD-containing spray improved pain as measured by different metrics like ‘pain severity’. The CBD-containing spray was generally well tolerated and showed no loss of effect.
Important to note here is that the used spray contained significantly higher concentrations of THC than is found in the average CBD oil. The question remains as to how much of these painkilling effects can be attributed to CBD, THC, or to the combination of both cannabinoids.
CBD and Headaches like Migraine
Various studies also looked at the effects of cannabinoids on headaches like migraine and chronic cluster headaches.
For example, one study done in 2017 looked at the effects of two different cannabinoid formulations on migraine and cluster headache (7).
In phase 1 of the study, a group of 49 chronic migraine patients was given an oral dose of THC and CBD. The approximate THC to CBD ratio of the oral dose was 2:1 for THC:CBD (the exact percentages were 19.4% THC and 9% CBD). The outcome was that doses of less than 100mg produced no effects. When an oral dose of 200mg was administered, the acute pain dropped by 55%.
In phase 2 of the study, 79 chronic migraine patients were given a daily dose of 200mg of the THC-CBD combination for a period of three months.
The severity and number of cluster headache attacks only fell slightly. However, the cannabinoid formulation reduced pain intensity among migraine patients by 43.5%.
Important to note here is that the used spray contained significantly higher concentrations of THC than is found in the average CBD oil. The question remains as to how much of these painkilling effects can be attributed to CBD, THC, or to the combination of both cannabinoids.
Now we know that there’s at least some scientific evidence indicating that CBD could be beneficial for pain relief.
But what makes CBD a potential painkiller? What’s CBD’s mechanism of action in human physiological processes?
How CBD Works for Pain Relief: CBD’s Mechanism of Action
CBD interacts directly with a variety of receptors like:
- CB1 and CB2 receptors;
- Glycerine receptors;
- Opioid receptors;
- Serotonin receptors;
- Adenosine receptors, and;
- TRPV1 receptors.
Some of these receptors and their neurotransmitters are associated with important pain-related physiological processes like pain-signaling and pain-sensation.
CBD’s interaction with these receptor systems is exactly what makes CBD oil a potential candidate for relieving symptoms of pain-related conditions.
When you ingest CBD, you can alter the functioning of some of these receptors.
The CBD inside CBD oil in some cases:
- Activates pain-related receptors, stimulating and increasing the activity of pain-reducing neurotransmitters that communicate with these receptors.
- CBD blocks these pain-related receptors. The blocking of pain-related receptors sometimes increases the presence of pain-reducing neurotransmitters in the brain by blocking re-uptake. And other times it leads to desensitizing of these receptors, decreasing the activity of pain-increasing neurotransmitters.
Current research shows that CBD has a strong affinity for interacting with 4 particular receptors that are associated with experiencing feelings of pain:
- Delta-opioid receptors;
- 5-HT1A (hydroxytryptamine) serotonin receptors;
- Adenosine receptors;
- TRPV1 receptors (vanilloid receptors). and;
- Glycine receptors.
Let’s explore these a bit further.
CBD and Its Interaction with Delta-Opioid Receptors
Opioid receptors are a set of receptors that are associated with important physiological processes like:
- Pain signaling in the central and the peripheral nervous system;
- Respiration, and;
- Immunological response.
Opioid drugs like morphine are highly effective as painkillers because they target opioid receptors.
And while CBD doesn’t target opioid receptors directly, different studies have shown that CBD acts as an ‘allosteric modulator’ to opioid receptors (8).
What this means in layman’s terms is the following:
CBD can increase the effectiveness of compounds that directly interact with opioid receptors (this is called allosteric modulation).
By increasing the effectiveness of opioid-receptor targeting agents, CBD could help with pain relief.
CBD and Its Interaction with 5- HT1A (hydroxytryptamine) Serotonin Receptors
Serotonin receptors and neurotransmitters are associated with a huge list of biological processes like:
- Pain perception;
- Sensory pain-processing at multiple levels within the central and peripheral nervous systems;
- Cardiovascular function;
- Bowel motility;
- Ejaculatory latency, and;
- Bladder control.
Serotonin is often referred to as a “feel-good neurotransmitter.” When serotonin neurotransmitters are active they can act as an anti-depressant, improving your general sense of well-being.
Now, here comes the interesting part about serotonin receptors and neurotransmitters:
Recent studies have found that the activation of 5-HT(1A) receptors (a specific type of serotonin receptor) can decrease chronic pain (9).
The exact mechanism of action needs further research …
But CBD is known to activate 5-HT(1A) serotonin receptors (10).
CBD’s potential to activate 5-HT(1A) receptors could be partially responsible for its analgesic (painkilling) effects.
CBD and Its Interaction with Adenosine Receptors
Adenosine receptors are associated with many biological functions like:
- Heart function;
- Regulation of myocardial oxygen consumption and coronary blood flow;
- Inflammation and immune responses throughout the body;
- Regulating the release of neurotransmitters such as dopamine and glutamate.
Adenosine signaling has been associated with anti-inflammatory effects.
Adenosine uptake is the primary mechanism that stops adenosine signaling.
Compounds that prevent adenosine uptake, promote adenosine signaling and thus promote anti-inflammatory effects.
Studies have shown that CBD increases adenosine A2A receptor signaling by inhibition of the adenosine transporter (11).
Researchers think that CBD’s affinity to bind to adenosine receptors is a mechanism of action that results in its anti-inflammatory properties.
CBD and Its Interaction with Vanilloid Receptor 1 (TRPV1)
Vanilloid receptor 1 (TRPV1) is also called the ‘capsaicin receptor’ because it gets activated by:
- Capsaicin (the irritating compound in hot chili peppers);
- A temperature greater than 109 °F (43 °C ), and;
- Acidic conditions.
Vanilloid receptor 1 is involved in processing various painful stimuli and the transmission and modulation of pain.
TRPV1 receptors work the opposite way of 5-HT(1A) serotonin receptors when it comes to pain. When they’re active, you experience a heightened sense of pain.
CBD has been shown to bind to (block) vanilloid receptors, blocking their activity.
Researchers have hypothesized that when CBD binds to vanilloid receptors it leads to the desensitization of TRPV1 receptors, which in turn, leads to painkilling effects (12).
CBD and Its Interaction with Glycine Receptors (GlyRs)
Glycine receptors are involved in inhibitory neurotransmission in the spinal cord and the brainstem.
What this means is that the activation of glycine receptors decreases neuronal signaling of specific neurons that are associated with motor control and pain perception.
CBD has been shown to activate glycine receptors and the activation of glycine receptors has been associated with a reduction in pain (13).
What’s the Best CBD Oil for Pain Relief?
The best CBD oil to explore CBD’s potential for pain relief is any full-spectrum CBD oil that’s packed with a variety of:
- Cannabinoids, and;
Hemp plants contain many other beneficial compounds besides CBD.
Cannabinoids like THC and CBG have been associated with painkilling effects. Hemp plants also contain terpenes, of which a few have been associated with painkilling effects as well.
All of these different cannabinoids and terpenes have beneficial effects in and of themselves, but more importantly, some researchers suggest that CBD works best in combination with other naturally occurring compounds (like other cannabinoids and terpenes) found in the Hemp plant, through a process they call ‘the entourage effect’.
A full spectrum or full-plant extract CBD oil makes the best case for the entourage effect and will let you experience CBD’s effects for improving pain in the most potent way.
In fact, as you’ll learn in the dosing paragraph: one study has found that full-plant extract CBD oil indeed is more potent than purified CBD products that only contain CBD.
For best effects, you want a CBD oil that’s biochemically as close as possible to the original biochemical composition of high-resin Hemp plants.
This means that your CBD oil should not only contain large concentrations of cannabinoids and terpenes but it should contain a wide spectrum of cannabinoids and terpenes.
For a current list of CBD oils that we recommend for exploring the potential benefits of CBD for pain relief, click the link below:
Are Topical CBD Products a Good Alternative to Oil When It Comes to Pain Relief?
Topically applied CBD may prove to be useful for certain pain-related conditions.
Although there are no human studies that looked at the effects of topically applied CBD on specific pain-related conditions, one animal study has found that topical CBD application significantly reduced pain and inflammation in rats with arthritis.
Topically applied CBD has also been found effective for inflammatory skin conditions and may help reduce pain associated with these types of skin conditions. For example, one study with 20 patients with two frequent skin disorders: psoriasis, atopic dermatitis found that CBD’s anti-inflammatory effects can provide significant relief (14).
While scientific evidence is scarce, anecdotal reports are plenty. CBD creams do seem to effectively relieve pain at least for some people.
But are topical CBD products like balms and creams more effective than oils/tinctures?
Without a properly conducted scientific study, we can’t say with certainty…
But in our subjective experience, a combination of both works best when it comes to certain types of pain like exercise-induced inflammation/pain.
How to Use CBD Oil for Pain Relief (Administration Methods)
Taking a full-spectrum CBD oil sublingually is our most recommended method to take CBD oil for pain relief.
- With edible CBD oils, it’s very easy and reliable to dose the exact amount of CBD you ingest;
- Full-spectrum, edible CBD oils are the most potent CBD products that you can get because they contain the widest variety of hemp-derived compounds of all CBD products, and;
- The effects last the longest (2-5 hours).
Taking CBD for pain relief through oral consumption also has a few downsides:
While the effects of taking CBD orally last longer compared to vaping, for example, the time before effects are at their peak take also significantly longer (2 to 4-hours compared to 5 to 15 minutes)
We always recommend taking your edible CBD oil sublingually to avoid the ‘first-pass effect’. The first-pass effect refers to the metabolization/reduction in the concentration of drugs and other substances before they reach the bloodstream. When you take CBD oil sublingually, at least part of the compounds inside will be directly absorbed through the mucous membrane beneath your tongue.
How you take your CBD oil sublingually is by keeping it under your tongue for at least 60 seconds, and only after that, swallowing it.
Another option you have is taking CBD gummies, although CBD gummies generally don’t contain as many and different hemp-derived compounds compared to oil/tinctures.
We wrote an extensive guide on the topic of the best methods to take CBD oil (including vaping CBD vape oil), which you can read below:
How to Dose CBD Oil for Pain
As CBD oil isn’t an officially approved medicine for pain conditions, there are no official dosage guidelines.
So where do you start?
The kidney transplant study (2) found painkilling effects of CBD with an initial dose of 100 mg/day and a progressive increase of up to 300 mg/day (spread out over the day in smaller doses).
Realize that with high doses like these, taking full-plant extract CBD oil is going to turn out expensive. For example, a NuLeaf Naturals CBD oil has a strength of 50mg CBD/milliliter. A 0.5 FL OZ (15ml) bottle of their pure CBD hemp oil contains 725mg of CBD and costs $70. If you’re going to take 100mg of CBD, a $70 bottle is only going to last you 7 days.
You might not need such a high dose, start with low amounts, especially if you’re using a full-spectrum CBD oil. There’s a study that showed epilepsy patients that used full-spectrum cannabis extract, needed 4-times less of a dose to improve their condition than epilepsy patients that used a purified CBD product (15). Something similar might hold true pain relief.
To find a high-quality full-spectrum CBD oil, go to our list of:
Whatever you do, never use more than 1500mg/day, this is the current maximum recommended dose according to several studies.
Also make sure that if you’re taking other medicines, be extra careful with high doses, as CBD could potentially interact with many pharmaceutical drugs and create various side effects.
Note that how many drops you need to take to achieve a set amount of CBD in milligrams, is highly dependent on the CBD oil that you’re using. CBD oils come in many different strengths with potencies of 1% CBD to 30% CBD.
For example, NuLeaf Naturals CBD oil has a strength of 50mg CBD/milliliter or 6.94%. A 0.5 FL OZ (15ml) bottle of their pure CBD hemp oil contains 725mg of CBD. In their case, 1 drop = 2.4 mg of CBD, which means there are 300-320 drops in total. Start with a full serving as recommended by the manufacturer. in the case of this particular oil, this would amount to 30mg of CBD + additional hemp-derived cannabinoids and terpenes.
Now, if you notice that your body doesn’t have any adverse reactions, you can slowly start to increase the dose IF you don’t feel any positive effects from your initial dose.
There are also dosage instructions that come with the CBD oil you purchase to read before taking that first dose. Continue taking up to the maximum amounts slowly over your first four weeks. Evaluate how it helps to relieve your symptoms, take notes, and journal. Keep in mind that peak effects of orally consumed CBD appear only after 2 to 4 hours.
If you do experience side effects like drowsiness, which is unlikely at lower doses, you may want to take CBD oil in the evening, just before bedtime. Or you could spread let’s say a dosage of 100mg CBD in smaller portions throughout the day. This is exactly the method that was used in the kidney-transplant study (2), which means this method of dosing has at least some scientific support.
For a guide on unofficial CBD dosages, click the link below:
- CBD Oil Dosages
How Long Does It Take for CBD Oil to Work for Pain Relief?
Again, commercially produced and sold CBD oil is not medicine.
That said, you can use anecdotal reports and the results of a few studies as a guide for knowing when to expect when using CBD oil.
The kidney-transplant study, for example, found that patients experienced positive effects within 15 days of daily CBD oil use.
Side Effects of CBD Oil
CBD has no known severe side effects. Opioid painkillers, in contrast, come with side effects such as overdose, increased likelihood of heart attack, and addiction.
The side effects associated with CBD use are minor and include:
- Dry mouth;
- A slight sedative reaction (feeling sleepy), and;
- A reduction in the liver’s ability to metabolize certain pharmaceutical medications .
For a non-exhaustive overview of currently known interactions of CBD and side effects, click here. Anyone taking a prescribed drug should speak with their healthcare provider before using CBD oil .
Is CBD Legal?
CBD oil that’s been extracted from hemp under the Farm Bill of 2014, and contains less than 0.3% THC, is legal to sell and purchase in all 50 states, with no doctor’s recommendation.
If you’re going to use CBD oil, always consult with your healthcare practitioner first, especially if you’re already taking prescription-based medicines. Be very careful when combining CBD oil with pharmaceutical drugs!
Check the article below to find the best CBD oils:
- CBD Oil Reviews
If you want to use a topical product, check out:
If you want to read up on more potential benefits of CBD, check out our article on:
If you want to become an expert on CBD oil in just 5 minutes, check out our guide on:
Lastly, if you want to connect with us, share this article/become a fan on Facebook or follow us on Instagram by clicking the links below
Xiong, W., Cui, T., Cheng, K., Yang, F., Chen, S. R., Willenbring, D., . . . Zhang, L. (2012). Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. Journal of Experimental Medicine, 209(6), 1121–1134. https://doi.org/10.1084/jem.20120242
Cuñetti, L., Manzo, L., Peyraube, R., Arnaiz, J., Curi, L., & Orihuela, S. (2018). Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplantation Proceedings, 50(2), 461–464. https://doi.org/10.1016/j.transproceed.2017.12.042
Hasenoehrl, C., Storr, M., & Schicho, R. (2017). Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go? Expert Review of Gastroenterology & Hepatology, 11(4), 329–337. https://doi.org/10.1080/17474124.2017.1292851
Pagano, E., Capasso, R., Piscitelli, F., Romano, B., Parisi, O. A., Finizio, S., . . . Borrelli, F. (2016). An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse. Frontiers in Pharmacology, 7. Published. https://doi.org/10.3389/fphar.2016.00341
Hammell, D., Zhang, L., Ma, F., Abshire, S., McIlwrath, S., Stinchcomb, A., & Westlund, K. (2015). Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. European Journal of Pain, 20(6), 936–948. https://doi.org/10.1002/ejp.818
Johnson, J. R., Lossignol, D., Burnell-Nugent, M., & Fallon, M. T. (2013). An Open-Label Extension Study to Investigate the Long-Term Safety and Tolerability of THC/CBD Oromucosal Spray and Oromucosal THC Spray in Patients With Terminal Cancer-Related Pain Refractory to Strong Opioid Analgesics. Journal of Pain and Symptom Management, 46(2), 207–218. https://doi.org/10.1016/j.jpainsymman.2012.07.014
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Bardin, L. (2011). The complex role of serotonin and 5-HT receptors in chronic pain. Behavioural Pharmacology, 22(5 and 6), 390–404. https://doi.org/10.1097/fbp.0b013e328349aae4
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Carrier, E. J., Auchampach, J. A., & Hillard, C. J. (2006). Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression. Proceedings of the National Academy of Sciences, 103(20), 7895–7900. https://doi.org/10.1073/pnas.0511232103
Costa, B., Giagnoni, G., Franke, C., Trovato, A. E., & Colleoni, M. (2004). Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. British Journal of Pharmacology, 143(2), 247–250. https://doi.org/10.1038/sj.bjp.0705920
Xiong, W., Cui, T., Cheng, K., Yang, F., Chen, S. R., Willenbring, D., . . . Zhang, L. (2012b). Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. Journal of Experimental Medicine, 209(6), 1121–1134. https://doi.org/10.1084/jem.20120242
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Post last updated on: March 4, 2022
Reviewing vaporizers, growing supplies, CBD products and scientific articles about cannabis, cannabinoids, and vaping since 2012. Read more about Winston here. LinkedIn
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Repeated CBD Doses Required for Effective Pain Relief
Repeated administration of cannabidiol (CBD) is needed to reduce neuropathic pain and related anxiety, new research suggests.
In a study designed to evaluate the dose, treatment duration, and mechanism of action of CBD, the drug modulated nociception, decreased anxiety-like behavior, and increased serotonin activity in a rodent model of neuropathic pain.
CBD also acted on some specific receptors but not others, a finding that paves the way for future therapeutics based on this active component of cannabis.
“These results are clinically relevant, as CBD is known to exhibit few side effects and supports the initiation of clinical trials testing the efficacy of CBD-based compounds for treating neuropathic pain and comorbid mood disorders,” the investigators write.
One-time acute treatment is likely insufficient.
“The most effective neuropathic pain relief occurs after 1 week of daily CBD treatment,” senior author Gabriella Gobbi, MD, PhD, professor of psychiatry, Neurobiological Psychiatry Unit, McGill University, Montreal, Canada, told Medscape Medical News.
Using in vivo electrophysiology, these experiments demonstrated that CBD decreases serotonin firing after an acute injection. However, after 1 week of treatment, the firing of serotonin increased through the desensitization of the 5-HT1A receptor.
This is the same mechanism observed for selective serotonin reuptake inhibitors, which “also require a few days or weeks before having a therapeutic effect — likely because some neuroplastic event occurs at the level of the receptors,” Gobbi said.
“Translating this to a clinical setting, these results suggest that the best treatment with cannabidiol will be a chronic treatment, but further clinical studies have to confirm this,” she added.
The findings were published online in Pain.
Growing Research Interest
Research interest in CBD, a noneuphoric and nonaddictive cannabis component, is growing. Investigators are assessing a wide range of potential indications, including treatment of chronic pain, nausea, psychosis, and anxiety, as well as epilepsy.
In addition, in June, the US Food and Drug Administration (FDA) approved a purified formulation of CBD (Epidiolex oral solution, GW Pharmaceuticals) to treat two rare forms of epilepsy.
The current study is not the only one to evaluate CBD for the treatment of neuropathic pain. Previous researchers assessed CBD alone or in combination with tetrahydrocannabinol for this indication.
However, few studies have explored the effect of CBD on 5-HT neurotransmission in the dorsal raphe nucleus (DRN), Gobbi and colleagues write. This region of the brain is important because it is involved in both mood disorders and pain, they note.
The investigators studied 229 adult male Wistar rats. They assessed the effects of both acute CBD therapy and repeated low-dose CBD on neuropathic pain modulation and responses.
Through a series of tests, they studied the firing activity of neurons, nerve desensitization, and reactions to mechanical allodynia. They also evaluated behavior using an open field test, a forced swim test, an elevated plus maze test, and a novelty-suppressed feeding test.
Electrophysiologic recordings demonstrated that neuropathic pain provoked a maladaptation of 5-HT neurotransmission. This action in turn caused a decrease in the firing activity of spontaneously active DRN 5-HT neurons.
The investigators also sought clarity on an effective dose of CBD. CBD has been used therapeutically in doses ranging from 2.85 to 50 mg/kg/day, “meaning that its therapeutic dose is still unclear,” the researchers note.
For acute treatment, they administered cumulative injections of 0.05 to 0.25 mg/kg of CBD and 10 to 50 mg/kg of D-lysergic diethylamide acid (LSD). They also administered a single injection of the 5-HT1A antagonist WAY 100635, the AM 251, and/or the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine.
By pretreating with these antagonists and then administering CBD, the investigators demonstrated that the 5-HT1A and TRPV1 receptors are involved in the agent’s mechanism of action and ruled out involvement of the CB1 receptor.
Repeated treatment showed that the lowest IV CBD dose needed to cause a significant decrease in 5-HT neuronal activity was 0.10 mg/kg. The difference was significant compared with vehicle preinjection in Bonferroni post hoc analyses (n = 9; P < .05).
In addition, a 0.25-mg/kg dose of CBD “completely shut down neuronal activity” (n = 9 ; P < .001), the researchers report.
Using the spared nerve injury model of neuropathic pain, “we found that repeated CBD treatment was able to prevent mechanical allodynia and anxiety-like behavior in rats experiencing neuropathic pain, but through different mechanisms,” they write.
The investigators note that TRPV1 channels were required for the antiallodynic but not the anxiolytic effects of CBD. In contrast, 5-HT1A receptors were required for the anxiolytic and, to a lesser extent, the antiallodynic effects of CBD.
These receptors are essential because multiple studies have demonstrated “that the 5-HT1A receptor is crucial for the mechanism of anxiety and depression relief,” Gobbi said.
“Very Surprising” Results
Gobbi noted that in the past 15 years, investigators have conducted many preclinical studies with THC, CB1 agonists, and fatty acid amide hydrolase inhibitors or endocannabinoid enhancers. However, “it was very surprising to see that CBD has a mechanism of action that is different from its ‘cousin’ drugs.”
The preclinical findings of this research support future clinical trials, Gobbi added.
“These animal studies suggest the indication for CBD use in humans’ neuropathic pain and comorbid anxiety,” Gobbi said. “We have a better idea about the doses in humans, [because] the FDA has conversion tables to translate doses from animals to humans, and. we know more about the length of treatment.”
Could the findings have new implications, given recent government approvals for use of cannabis? “I hope so,” she answered.
“Canada has legalized recreational cannabis and made medicinal cannabis more accessible, but little is yet known about medical cannabis. A lot of patients are using mixtures of THC [and] CBD without knowing the appropriate indications, doses, side effects, and interactions with other drugs,” Gobbi noted.
“This research — I hope — will encourage more systematic medical cannabis research to help patients and doctors to make more evidence-based choices,” she said.
Commenting on the findings for Medscape Medical News, Yasmin Hurd, PhD, professor of neuroscience, psychiatry, and pharmacologic sciences, Icahn School of Medicine at Mount Sinai, New York City, said this is an interesting study “that provides strong preclinical findings in support of the antinociception and antianxiety effects of CBD relevant to the condition of neuropathic pain.”
Hurd added that she applauds the investigators’ use of multiple approaches — behavioral, pharmacologic, and electrophysical measurement of cell firing — because this strengthened the overall findings. She also said the research strategy provided insights about the different biological mechanisms associated with CBD’s analgesic and anxiolytic properties.
“Clinical trials are of course still necessary, but the findings suggest that CBD may be potentially beneficial as a future treatment in reducing chronic pain and anxiety, which are often comorbid in neuropathic pain and related conditions,” she said.
Hurd, who was not affiliated with this study, has authored a review article on the potential role of marijuana as an alternative to opioids for the treatment of addiction.
When also asked by Medscape Medical News to comment on the study, Joshua Aviram, PhC, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel, was less enthusiastic.
“Although mechanistic observations on animal models are critical to the understanding of phytocannabinoids activity, human chronic pain is much more complicated than the mere nociception process,” Aviram said.
“Until these findings can be substantiated in high-quality controlled trials or even cohort studies on chronic pain patients, no responsible clinical implications can be drawn from these findings on CBD activity,” he added.
Aviram, principal investigator of a systematic review and meta-analysis on the efficacy of cannabis-based medicines for pain management, was not affiliated with the current study.
The study was supported by a matching grant from the Ministere de l’Economie Science et Innovation du Quebec and Aurora Cannabis Inc. Dr Gobbi, Dr Hurd, and Mr Aviram have disclosed no relevant financial relationships.
Pain. Published online August 27, 2018. Abstract
Follow Damian McNamara on Twitter: @MedReporter.
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Medscape Medical News © 2018
Cite this: Repeated CBD Doses Required for Effective Pain Relief – Medscape – Nov 02, 2018.
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