October 13, 2023

Nightshades Series 3 of 5: Peppers and Capsaicin

See previous article (2 of 5) of the Nightshades Series for more of a background on the nightshade/Solanaceae family. This article will be indicting all peppers— bell, chile, hot, sweet, banana, jalapeno, chipotle, Tabasco, paprika, etc.—if it has pepper in the name, it’s in this group. Peppercorns, Piper nigrum, are not in the Solanaceae family and are okay, especially if they are fresh ground. Pre-ground black pepper grows aflatoxin-producing Aspergillus flavus mold like crazy and is a gastrointestinal irritant, I’d suggest avoiding it.

Spicy food. Some of us hate it (consider yourselves lucky), some of us love it. As a former spicy food junkie (I proposed to my wife at our favorite Mexican food restaurant, we went there mainly due to the salsa!), this was the most painful part of the nightshade discovery for me, pun absolutely intended!

First off, I’ll be up front. I’m going to say that peppers inhibit proper healing, cause or worsen pain and disease through their own unique mechanisms (even within the nightshade family), and that the current medical “understanding” of the capsaicin/substance P relationship is wrong. Much of what I’m about to say, if my previous articles on this subject haven’t already made clear, is likely the exact opposite of what you’ll hear from conventional medicine and the media. It’s likely your physician (even the “alternative” types) will tell you that what I’m about to say is a bunch of BS and there is no research behind it. They would be wrong on both counts, which is too bad for them and their patients—at least you’ll be able to make an informed decision for yourself.

Pop quiz, hotshot—how many foods do you eat on a regular basis that cause you obvious pain if you eat too much of them? I’m going to guess it isn’t many, and spicy peppers are on that short list. If spicy peppers cause you to experience pain in your mouth, I’m going to suggest that G-d/Nature had a purpose for that, as in pain is typically a sign of something we should avoid! Hopefully, realizing this early will help make you less incredulous of what I’ll explain later.

Next, how many chemical compounds within a typical Paleo food list have an MSDS (Material Safety Data Sheet)? Well, capsaicin does! For those of you who didn’t already know, capsaicin and the capsaicinoid family are the “hot” chemicals in peppers. Taken directly from the MSDS on capsaicin:

“Potential Acute Health Effects:
Hazardous in case of skin contact (irritant, sensitizer), of eye contact (irritant, lung sensitizer). Severe over-exposure can result in death." [emphasis mine]

Here’s another “safety assessment” of peppers and their extracts. The true lethality of capsaicin is slowly becoming realized, with the increased use of pepper sprays and their associated deaths (an intensive summary of capsaicin in that link).

Right off the bat we have a known hazardous chemical, only found in spicy peppers, that causes pain, irritation, and death in extreme cases—and we’ve only just begun!

 

Capsaicin and Substance P

The following part is important and will involve minor forays into neurophysiology. Now, I’m no

neurophysiology expert, and to be quite honest, I find the fact that no one else seems to have been able to create the line of thinking and research I’m about to expound upon is quite disappointing. I’m going to try to make this as straightforward as I can.

Capsaicin is the main member of the capsaicinoid group of phytochemicals found within all spicy peppers (except bell peppers). Note in the “Uses – Medical” portion of that link, capsaicin is used in conventional medicine as a topical analgesic. Scoville units are the measuring units of the spiciness of peppers (the “pain” in your mouth when you eat them) attributable to capsaicin and related compounds. So, we can then infer that capsaicin, whether in peppers or isolated, interacts with our nervous system in very interesting ways (ie. burning pain in the mouth, eventual analgesia when applied topically).

Substance P is a neuropeptide that is theorized to be substantially involved in the pain mechanisms of spicy peppers. This association is because substance P is known to be involved in the transmission of pain impulses from peripheral nerves to the central nervous system and that capsaicin is a well-studied stimulator of substance P release, take for example:

From my own personal research into the subject, it would seem neurophysiologists don’t yet totally understand the complete picture of substance P in the human body, nor of the actual interaction processes of capsaicin and substance P in the chronic sense, either locally or (more importantly) systemically.

One of the (older) prevailing ideas as to how pain reduction is accomplished via topical capsaicin administration is through depletion of nerve ending supplies of substance P. Apply enough capsaicin over a long enough period of time and the nerve fibers are eventually depleted of their substance P stores. See the following studies:

So what does depletion of substance P mean? It means that the substance P dependent pain signal to the brain is “tired out,” that there are no more substance P messengers to tell the brain that the pain is still present; hence no pain sensation is perceived. Talk about only treating the symptoms! Another theory on the pain relief attributed to capsaicin and substance P that I have come across involved the degradation of the substance P receptors. I’d put my money on both mechanisms (depletion and receptor degradation) happening at the same time.

So, how does this all fit together in regards to inhibiting healing and increasing pain?

 

Feelin’ (Not So) Hot-Hot-Hot

So, we know that capsaicin and substance P are intertwined. How is substance P involved in healing?

A study looking at the Correlation between the Appearance of Neuropeptides in the Rat Trigeminal Ganglion and Reinnervation of the Healing Root Socket after Tooth Extraction found that:

“In the tooth sockets after extraction, new bone and a few SP-immunoreactive [substance P—author] nerve fibers were first seen at day 7, and bone completely filled the sockets at day 21...These findings suggest that the appearance of neuropeptides in the trigeminal ganglion, the reinnervation of SP-immunoreactive nerve fibers, and bone repair in the tooth socket during healing after extraction were correlated.”

So, it would appear that substance P nerve fibers appear early in the healing process.

If an area is lacking substance P nerve endings, how well does it heal? Looking at Neurogenic factors in the impaired healing of diabetic foot ulcers, we see that:

“Twenty patients with type 2 diabetes and active foot ulcers, without clinical evidence of peripheral sensory neuropathy (n = 12) and with sensory neuropathy (n = 8) were involved in this study...Lack of substance P nerve endings was characteristic for both groups...The observed reduction of foot skin innervation and neurogenic factors expression can be correlated with low inflammatory cell accumulation and subsequently leads to the observed chronicity of diabetic foot ulcer healing process in both neuropathic and non- neuropathic patients. [emphasis mine]

It would appear that a lack of substance P nerve endings leads to chronic poor healing.

What if exogenous substance P is given, such as in Adjuvant neuropeptides can improve neuropathic ligament healing in a rat model?

“First, we showed that neuropathy led to impaired healing of ruptured ligaments. We then showed that local delivery of specific neuropeptides could reverse the functional deficits of these neuropathic ligaments in only 2 weeks. In substance P and vasoactive intestinal peptide-treated medial collateral ligaments (MCLs), the mechanical properties of these healing neuropathic tissues returned to values at or above normally innervated, intact ligaments. [emphasis mine]

So administering substance P appears to reverse poor tissue healing, sometimes improving healing over their undamaged counterparts!

Capsaicin inhibits in vitro and in vivo angiogenesis. Angiogenesis is the formation of new blood vessels, which would be important after physical trauma to an area. Inhibiting that process would absolutely retard healing.

Oh yes, don’t let me forget the capsaicin/substance P/diabetes study that is so often misrepresented. Experts in the medical field (folks who have NO excuse) and the media have misrepresented the results and implications of this study, so we’ll absolutely forgive Mr. Scott Kustes for mentioning it in his otherwise fine article [link to that issue] on culinary herbs & spices. In the study, TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes, researchers injected substance P into Type I diabetic rats (note that it is not injected capsaicin!), and voila:

“Delivering the neuropeptide substance P by intra-arterial injection into the NOD [Non-Obese-Diabetic—author] pancreas reverses abnormal insulin resistance, insulitis, and diabetes for

weeks. Concordantly, insulin sensitivity is enhanced in TRPV1(-/-) mice, whereas insulitis/ diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin- responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology.”

Holy cow! Injecting substance P temporarily “fixed” Type I diabetes in rats! That’s just plain Black Box results right there! The problem was (even I misunderstood before I started my anti-nightshade crusade, so don’t feel bad Scott!) that everyone who didn’t understand the actual relationship between substance P and capsaicin interpreted the results somehow as capsaicin showing promise as a future diabetes cure. Hopefully you understand now that systemic applications of capsaicin (as in eating or injecting it) would do the exact opposite of the above study and deplete substance P systemically!

Uh-oh! Now spicy peppers could be implicated in insulin regulation problems? Stay tuned, true believers, as I explore this area more in next months issue…

Where’s the more direct connection to arthritis? Look in the diabetes study quote above, noting the part about how TRPV1 appears to play a role in our great capsaicin theater, as the TRPV1 receptor is stimulated by capsaicin. Here we have the Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis:

“Here, we demonstrate the expression of TRPV1 in synovial fibroblasts (SF) from patients with symptomatic osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, the mRNA expression of TRPV1 was shown in PBMCs from healthy controls and from OA patients. The presence of TRPV1 was confirmed at the protein level.”

We have confirmed expression and presence of TRPV1 in OA and RA fibroblasts. Write that down. Moving on...

“Stimulation of cultured OA- and RA-SF with the TRPV1 agonist capsaicin led to increased expression of IL-6 mRNA as well as of IL-6 protein in the cell culture supernatants. IL-6 protein expression could be antagonized with capsazepine. Thus, we hypothesize that TRPV1 may play a role in non-neuronal mechanisms that might modulate nociception in symptomatic OA and RA patients.”

So, stimulating arthritic fibroblasts with capsaicin causes an increased expression of pro-inflammatory IL-6! Not so good.

In the same vein as the substance P progression above, what about arthritis development in TRPV1 receptor. “knockout”, aka TRPV1R-/- mice, as in mice that don’t have that particular receptor?

Attenuation of experimental arthritis in TRPV1R knockout mice.

“The aim of our study was to determine whether TRPV1Rs play a role in the development and maintenance of inflammation and mechanical hyperalgesia by studying the development of unilateral joint inflammation in TRPV1R-/- mice… These results suggest that TRPV1 receptors are important for the development of joint inflammation and the associated mechanical hypersensitivity observed in this model.” [emphasis mine]

Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation.

“OBJECTIVE: To investigate the endogenous involvement of transient receptor potential vanilloid 1 (TRPV1) in a model of knee joint inflammation in the mouse…CONCLUSION: Our findings indicate that TRPV1 has a role in acute and chronic inflammation in the mouse knee joint. Thus, selective antagonism of TRPV1 should be considered as a potential target for treatment of acute and chronic joint inflammation.” [emphasis mine]

Capsazepine (a synthetic analogue of capsaicin that is antagonistic to the TRPV1 receptor) also has some research behind it, showing that it demonstrates anti-hyperalgesic properties in The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain.

“These data show that VR1 antagonists have antihyperalgesic activity in animal models of chronic inflammatory and neuropathic pain...”

Here we go with reduced blood flow again. Capsaicin- induced vasoconstriction in the mouse knee joint: a study using TRPV1 knockout mice.

“...in the present study we have shown that capsaicin produces a dose-dependent vasoconstrictor effect in the mouse knee joint via Transient Receptor Potential Vanilloid 1 (TRPV1) receptor activation. A (125)I-albumin accumulation technique showed that the intravascular volume of capsaicin-treated joints in wild type (WT) mice was significantly reduced compared to TRPV1 knockout mice (p<0.01). Similarly, a laser Doppler technique showed significantly reduced blood flow in the capsaicin-treated joints of WT compared to TRPV1 knockout mice (p<0.001).

In conclusion, I have attempted to establish here:

  • Capsaicin is already well known to be an irritant of the skin, respiratory system, and can cause death in excessive doses.
  • Capsaicin causes release and eventual depletion of substance P from nerve endings, possibly degrading the substance P receptors in the process.
  • Substance P nerve endings are necessary for truly proper, complete, and expedient healing.
  • Injections of substance P have been shown to improve connective tissue healing and type I diabetes.
  • Capsaicin has been shown to inhibit angiogenesis and reduce blood flow within joints.
  • Capsazepine, the capsaicin antagonist, has been demonstrated to reduce IL-6 and hyperalgesia associated with capsaicin administration.
  • TRPV1 receptors are found in arthritic fibroblasts and are very associated with the major processes of joint inflammation linked to capsaicin.

I hope the trail above was easy enough to follow. My suggestion would be to avoid all doses of capsaicin, whether topically or systemic. That means don’t eat peppers or use capsaicin-based creams! If a food is referred to as “spicy”, that’s a good sign you want to stay away. As I mentioned before, I’ll be back with more on peppers in the next blog article.

Written by Alexander Wilkinson