A Sensory Journey To The Heart Of Pain

A Sensory Journey To The Heart Of Pain

Posted by Nootropics Depot on 23rd Aug 2022

Learn all about what pain is, how we experience it, and what you can do to manage it..

Pain Is Complex

Pain is an incredibly complex experience, made up of hundreds of different sensory neurons firing together, creating electrical currents riding around at breakneck speeds on heavily myelinated neurons. Once these electrical currents reach our brain, they get parsed out into various brain regions such as the periaqueductal gray, insular cortex and amygdala. We then ascribe meaning to these electrical currents, and the subjective experience that results is what we refer to as pain.

This makes pain a very interesting but difficult to understand process, because pain can be amplified by our vision (seeing an injury occur) and even emotional states. This does open up many novel doors for dealing with pain though, and that is what we will be discussing in this blog! While the mechansims might be complex, we will be simplifying things down to help everyone understand the situation a bit better. We will also discuss how different traditional plants have been used to address pain in cultures around the world.

Pain Is Complex

Pain is an incredibly complex experience, made up of hundreds of different sensory neurons firing together, creating electrical currents riding around at breakneck speeds on heavily myelinated neurons. Once these electrical currents reach our brain, they get parsed out into various brain regions such as the periaqueductal gray, insular cortex and amygdala. We then ascribe meaning to these electrical currents, and the subjective experience that results, is what we refer to as pain.

This makes pain a very interesting but difficult to understand process, because pain can be amplified by our vision (seeing an injury occur) and even emotional states. This does open up many novel doors for dealing with pain though, and that is what we will be discussing in this blog!

Pain Is Complex

Pain is an incredibly complex experience, made up of hundreds of different sensory neurons firing together, creating electrical currents riding around at breakneck speeds on heavily myelinated neurons. Once these electrical currents reach our brain, they get parsed out into various brain regions such as the periaqueductal gray, insular cortex and amygdala. We then ascribe meaning to these electrical currents, and the subjective experience that results, is what we refer to as pain.

This makes pain a very interesting but difficult to understand process, because pain can be amplified by our vision (seeing an injury occur) and even emotional states. This does open up many novel doors for dealing with pain though, and that is what we will be discussing in this blog! While the mechansims might be complex, we will be simplifying things down to help everyone understand the situation a bit better. We will also discuss how different traditional plants have been used to address pain in cultures around the world.

What is Ashwagandha?

Ashwagandha is a herb that belongs to the night shade family of plants. The nightshade family of plants is a very interesting one and includes a lot of vegetables that make up large parts of many diets. Notable nightshade members are potatoes, tomatoes, chili peppers, goji berries and even tobacco! Another name for the nightshade family is Solanaceae. This is where Ashwagandha gets its Latin name from; Withania somnifera. Ashwagandha is a short perennial shrub, with a large root system that develops small deep orange fruits. The fruits resemble a small cherry and the leaves look frosty due to the many tiny hairs that are on them. This one of the reasons why Ashwagandha is also referred to as ‘winter cherry’. Traditionally, the Ashwagandha root is used, however new research has found high concentrations of key components in the leaves too. Various manufacturers have taken notice of this. One of the most notable being Natreon who produce a specialized extract of Ashwagandha called Sensoril. Sensoril is made from the leaves of Ashwagandha, giving it a unique chemical composition, which produces noticeable calming effects.

A Painful Touch

The most fascinating aspect of pain is how deeply intertwined it is with our sensory experience of the world. The same receptors that allow us to feel different temperatures, vibrations, textures, etc. are the same exact receptors that produce nociceptive signals. Think of it like this. If you take a warm shower at a very comfortable temperature, it can be very relaxing. This is because at very low levels it is activating receptors such as TRPA1 and TRPV1, which we perceive as a pleasant warmth. However, if we crank up the temperature of our shower, this pleasant warth quickly turns into a painful sensation on the skin. This is because at higher temperatures, heat sensitive receptors such as the TRPV1 receptor send out much stronger electrical signals, which our brain then interprets as pain. This is very important, as it allows us to exit the stream of hot water before any tissue damage occurs.

With this in mind, we need to embrace pain if we want to handle pain. At the very core, pain is a great thing. If our TRPV1 receptors didn’t send out strong signals in response to a shower temperature that is much too high, then we would stay under the stream of hot water and perhaps incur some very low grade burns. The issue with pain however arises when there is no risk of injury, and the pain persists. When our sensory systems are working properly, this shouldn’t happen, and pain should be a very precise tool for keeping ourselves safe. Yet oftentimes the pain is dull, doesn’t protect us from anything, and can make life miserable. Let’s dive a little deeper into why this happens!

Plastic Pain

When we experience an injury, we also experience high degrees of neuroplasticity. This is a change in the neural network of your brain in reponse to stimuli. Let’s look at a personal experience with an injury to better illustrate this process. I recently cut a decent chunk off my index finger with a mandolin slicer. If you have ever been told by someone to give a mandolin slicer massive amounts of respect, it’s true! It’ll rob you off your fingertips without you even realizing it! This is because the blade is extremely sharp, which makes for a very clean and fast cut, liberating yourself of the nociceptive nerve endings on the fingertip. There is a seemingly big delay in the nociceptive signals reaching the brain. What I saw first was just blood, and for about 5 minutes all I experienced was a sharp but very manageable stinging. It wasn’t until a few hours later when the pain really started to set in. Why is this?

At the site of injury, my fingertip was flooded with an “inflammatory soup” full of pro-inflammatory compounds like interleukins, prostaglandins, and nerve growth factor (NGF). This inflammatory soup then makes various nociceptive receptors such as TRPV1, NaV 1.7, NaV 1.8 and various voltage gated calcium channels much more sensitive, which then cause progressively stronger nociceptive signals to be sent out to the brain. This is one of the reasons why the pain gradually builds after a minor injury. Now this is where it starts to get interesting though, because within that inflammatory soup we now have lots of NGF. This flood of NGF in my fingertip then causes the nociceptive neurons to become more sensitive, meaning that my fingertip is now much more sensitive to things temperature changes and mechanical impacts. For example, lukewarm water felt like boiling water after the injury. This is a great adaptive response though, because my focus was constantly on my injured finger due to the newly gained nerve endings in my finger that are ultra sensitive to inputs from the outside world. This allowed me to keep the injured finger safe, speeding up the healing process. However, this process can also go a little bit awry, which, unfortunately I also experienced.

During the injury, I experienced a highly increased sensitivity to impacts. Normally, if I tap my finger tip against a surface, like typing out these words you are reading, I don’t feel a whole lot except for the clack of the keys. When the injury was fresh however, the tiniest little touch felt excruciatingly painful, and typing with the injured finger was certainly out of the question. Annoyingly, it is now a few months later, my finger has been healed for a long time, yet every time my previously injured finger hits a key, I feel a sharp jolt of very mild pain, despite there being no injury and no risk of opening up the injury. This is likely because the injury was bad enough to cause high amounts of neuroplasticity in my fingertip, and the extra nerve endings and sensitivity will take a while to go away. Now with my finger this is no big deal, it is just a minor inconvenience. However, the same process can happen with much larger injuries like back injuries, shoulder injuries, knee injuries, etc. This extra sensitivity to pain can last for a very long time, and can be quite debilitating. Thus, when we talk about pain management, we are often talking about dealing with the remnants of injury induced neuroplasticity!

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Reversing The Plasticity: Lifestyle & Topicals

One of the best ways then to deal with pain is likely to try and reverse this neuroplasticity. Experimental procedures have utilized this method for a long time, applying strong electrical currents to nerves to desensitize them for example. More mild examples of this include acupuncture, massages, foam rolling, mild electrical stimulation, application of capsaicin, application of menthol, application of camphor, exposure to extreme cold temperatures etc. All of these factors have one thing in common: they can all stimulate nociceptive nerves, and by doing this, may even be able to desensitize them. For example, if I were to tap my fingertip on a surface for an hour a day, very repetitively, then perhaps I can desensitize the receptors that respond to mechanical impacts and my fingertip will be back to normal sensitivity levels.

If, on the other hand, my fingertip had increased sensitivity to hot temperature, I could consider applying topical capsaicin to my finger tip. Capsaicin activates TRPV1 receptors which normally detect heat, and at sites of injuries, TRPV1 receptors often become upregulated. Thus, by applying a TRPV1 agonist, I could then experience a bit of relief, as it would hyper-activate the TRPV1 receptor, which should quite rapidly desensitize them, thus leading to more normal levels of sensitivity which translates to a pain management effect. Due to this effect, you sometimes see capsaicin being included in topical pain management ointments. On the flipside, you also often see menthol and camphor in topical pain management ointments, sometimes even combined. Tiger balm is a famous example of this, and the menthol content in it activates cold receptors (TRPM8) while the camphor content activates TRPV1 receptors. The combined effect is a mild, yet palpable pain management effect, which is directly mediated by receptors located on nociceptive neurons.

Similarly, heat and cold are also often applied to sore areas. The cold of an ice pack, similar to menthol, will activate cold receptors. A heat pack on the other hand, would activate TRPV1 receptors. A hot or cold shower can also have an effect on these receptors. It’s interesting to consider that these are often the first lines of defense against pain, and we are actually directly influencing nociceptive signaling with these strategies. In addition to this, these can be great techniques to help reverse some of the long lasting neuroplasticity mediated pain by getting the nociceptive neurons to a normal level of sensitivity

Reversing The Plasticity: Inflammation Regulating Supplements

In addition to physically interacting with the nociceptive neurons, by stimulating them with massages, ointments, heat exposure, cold exposure etc. we can also influence this plasticity mediated pain with oral supplements! Let’s start with the lowest hanging fruit, inflammation!

As we talked about earlier in the blog, at the site of injury we often see an influx of an “inflammatory soup” which contains various pro-inflammatory compounds such as the interleukins and prostaglandins. These pro-inflammatory compounds also make our nociceptive neurons more sensitive, and thus, reducing inflammation is one of the most common ways in which to deal with pain. Luckily, there are a TON of different supplements with really excellent inflammation regulating effects. One of the most popular pain management supplements that influences pain via the inflammation pathway, is without a doubt curcumin. Curcumin inhibits an enzyme called cyclooxygenase 2 (COX-2) which is an enzyme that produces a lot of the inflammatory prostaglandins. By inhibiting its activity, curcumin does a great job of mitigating high levels of inflammation. However, curcumin is not alone in this category, and in fact, a lot of plants/compounds can have major inflammation regulating effects, here are a few more of our all time favorites:

Andrographis paniculata 

Nigella sativa




By successfully lowering overall inflammatory tone, you have a much better chance of overcoming the increased sensitivity in painful areas that remain painful long after the injury has been resolved. In addition to this, inflammation regulating compounds may even help dampen some of the sensitization if taken when an injury is active. It’s also a great way to mitigate the pain associated with an active injury as you would be dampening the overall inflammatory soup which causes us issues!

Reversing The Plasticity: Oxidation Regulating Supplements

Within the inflammatory soup, we also often find high concentrations of cytokines which induce oxidation, which then further contribute to inflammation mediated pain sensitization. With this in mind, controlling oxidative stress is then also a great strategy for mitigating nociceptive sensitisation. One of our favorites for this purpose is tart cherry, which produces a fantastic oxidation regulating effect, while also reducing uric acid levels. Uric acid also appears to play a role in pain, and thus, tart cherry is one of the best oxidation focused pain supplements around! Some of our other favorites are:

Reduced glutathione


Green Tea Extract


Vitamin E

By controlling oxidative stress, we can actually limit quite a bit of the sensitisation effect, and due to this, we believe that the best pain management stacks also need an oxidation regulating element in it. However, this aspect of pain is often overlooked, with their being a much stronger focus on inflammation. Oxidation and inflammation go hand in hand with long term pain, and thus utilizing this phenomenon will make pain management a lot more successful!

Reversing The Plasticity: Endocannabinoid Supplements

Our endocannabinoid systems also play a huge role in how we process pain, and even plays a role in pain sensitisation. Endocannabinoid compounds such as anandamide, 2-AG, and even palmitoylethanolamide interact with pain in very comprehensive ways. First of all, most of the endocannabinoids have robust inflammation and oxidation regulating effects. Furthermore, they bind to and activate CB1 and CB2 receptors, which directly influence the intensity of nociceptive signals. With this in mind, optimizing our endocannabinoid system is a fantastic pain management strategy.

The easiest way to dial in our endocannabinoid systems is simply to consume more essential omega-3 fatty acids, specifically DHA and EPA. Both DHA and EPA serve as endocannabinoid precursors, but unfortunately a lot of us are deficient in DHA and EPA; especially vegans and vegetarians. The overall result this can have is lower endocannabinoid activity, which can leave us much more susceptible to pain. Thus, by consuming high quality fish oil supplements like AvailOM high EPA or AvailOM high DHA, you can dial in your endocannabinoid system which can help make you more resistant to pain!

Another extremely popular pain supplement that focuses on the endocannabinoid system is palmitoylethanolamide (PEA). PEA actually is an endocannabinoid, and unlike most of the other endocannabinoids, can be taken orally as a supplement. It takes a little while for PEA to become effective, because first you need to build up PEA levels in your body. However, once PEA levels reach a certain level, endocannabinoid activity is significantly upregulated and this translates to a very robust pain management effect. Some of our other favorite endocannabinoid focused pain supplements are:






Reversing The Plasticity: Neuroactive Supplements

Last but not least, let’s go all the way up the pain chain, to the brain! As we briefly touched on earlier, “pain” is simply a nociceptive signal that we then ascribe meaning to within our brain. This means that mental states can have an enormous impact on the experience of pain. It’s hard to believe, but having a more positive attitude about the pain you are experiencing can actually help reduce your subjective experience of pain. This is not always easy to do, especially because long term pain can dramatically impact our mood. With this in mind, mood boosting supplements, especially those which possess pain management effects, can be very useful in pain management!

In terms of receptor targets, this starts to get a little bit complicated because a lot of neurotransmitters are involved with the processing of pain. For example, serotonin is highly involved, which is why raising serotonin levels with serotonin reuptake inhibitors like saffron can have a robust pain management effect. This may then also have to do with our mood state and how we interpret the incoming nociceptive signals. Similarly, elevating dopamine levels with a dopamine reuptake inhibitor like sabroxy can have a major impact on pain processing.

Two of the most important receptors for pain processing however are the NMDA receptor and voltage gated calcium channels, both of which also happen to work hand in hand. When NMDA activity is up, calcium related activity is up too, and this can make us more sensitive to nociceptive signals. This is also why inhibiting NMDA receptors and calcium channels is one of the most utilized methods for dealing with pain. One of our favorites for the purpose of inhibiting NMDA signaling is our new stack, Clarimag. Clarimag contains magnesium, which is an NMDA inhibitor in addition to Polygala tenuifolia and agmatine which both inhibit NMDA receptors too.

Some of our other favorite neuroactive supplements for pain management are:

Kava: For activating CB1 receptors and GABA receptors while also blocking calcium channels. The mood boost from kava also has a wonderful effect on how we interpret and deal with pain on an emotional level.

Magnolia Bark: Similar to kava, magnolia bark has effects on endocannabinoid function and GABAergic signaling.

Lemon Balm: Enhances GABAergic tone by inhibiting GABA transaminase, an enzyme which breaks down GABA. Through this action, it can have mild muscle relaxant and mood boosting properties.

Matrine: For activating kappa opioid receptors

DL-Phenylalanine: For increasing dopamine and endorphin levels

Bringing It All Together: Pain Stacks

Now that we have a solid understanding of what pain is and how pain processing can be influenced, it is time to make that knowledge practical! We made three different pain stacks, one simple pain stack for beginners/low grade pain, one more comprehensive stack for intermediate/medium grade pain and one ultra-comprehensive stack for advanced/higher grade pain!

"Research has shown that magnesium levels are decreasing in most foods... With the magnesium content decreasing in crops and the increase in the consumption of processed foods, magnesium deficiencies in the population are becoming more prevalent."

Beginner Pain Stack

This simple stack mainly deals with the “inflammatory soup” by reducing pro-inflammatory compounds via longvida, while also mitigating oxidative stress with Na-R-ALA. This should result in a robust pain management effect which is perfect for minor and non-specific pain.



Intermediate Pain Stack

This intermediate stack combines two of the strongest natural inflammation regulating products, Andrographis paniculata and Longvida. These both mitigate inflammation via different mechanisms and thus the effects are quite synergistic. In addition to this, we add in Rephyll which has a great effect on endocannabinoid signaling by activating CB2 receptors. In addition to this, rephyll also has a direct inflammation and oxidation regulating effect.




Advanced Pain Stack

For the advanced pain stack, we wanted to create the most comprehensive protocol possible which involves both lifestyle factors, topicals and supplements. The supplements have also been split into day and night supplements, because pain can often change dramatically from day to night, and this should be accompanied by different strategies.

The Morning Protocol

Upon waking, take a contrast shower. A contrast shower consists of bursts of very hot and very cold water. You need to work yourself up to the temperature extremes, so start slow! Start by getting under a comfortably hot shower, then turn it up just enough to where the heat becomes borderline unpleasant. Stay under this hot stream for about 1 minute. Then switch the water to a cold stream, getting it to where it is comfortable and then turning down the temperature just a little bit more until it is slightly uncomfortable. Stay under the cold stream for about 30 seconds. After 30 seconds, switch back to the hot stream. By doing this, you are consistently stimulating nociceptors all over your body while also increasing blood flow. The more accustomed you get, try and push the cold temperatures down to as cold as you can handle it and keep increasing the temperature on the hot water too (within reason of course, you don’t want to burn yourself!). End the shower with a burst of ultra cold water! When you finish your contrast shower, you may already notice quite a relief in muscle tension and overall soreness.

Next, if you have time in the mornings, do a bit of light stretching after the contrast shower, and follow up the stretching with some light foam rolling. This will help stimulate your mechanical nociceptors that respond to physical pressure and stretching.

Next, apply a topical product that contains either capsaicin, menthol, camphor or combinations of these to areas that feel sore. Bringing everything together, a contrast shower + stretching + foam rolling + topicals should push pain into a much more manageable place. This is now where we add in our morning stack.

Morning Stack: Longvida + Palmitoylethanolamide + AvailOM high EPA + Matrine + Sabroxy + Clarimag







The Evening Protocol

For individuals that deal with a lot of pain, nighttime can often be the worst. The strain of the day really takes a toll on you at the end of the day, and the pain can often result in restlessness and difficulty getting to sleep. Due to this, the evening stack is focused more on muscle relaxation which is being provided by kava. We then also add in Andrographis which has a phenomenal inflammation regulating effect, but with a unique trick up its sleeve. Andrographis activates TRPV4 receptors, which produces a pain management effect (specifically pressure focused pain) but in addition to this, also increases melatonin production. To further increase the melatonin effect, we also added in some plain low dose (0.3 mg) melatonin. Melatonin has a fantastic oxidation regulating effect and does a great job of controlling inflammation, while also helping to improve sleep quality. All great effects when it comes to controlling night time pain! We then also add in tart cherry, which by lowering uric acid levels can have a sleep promoting effect, in addition to having a positive impact on oxidation and general soreness. Last but not least is an endocannabinoid called oleamide, which has serotonergic effects and activates CB1 receptors. Oleamide has a great effect on inducing sleep too and is actually released endogenously right before we fall asleep!

By increasing relaxation at night and utilizing sleep promoting supplements, nights should be a lot more restful! This should also carry over into the next day, because better sleep also results in lowered perception of pain.

Evening Stack: Andrographis paniculata + Tart Cherry + Kava + Oleamide + Melatonin + Agmatine








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