Last month’s PMenu article on Capsicum peppers covered mechanisms by which capsaicin (the “active” ingredient in peppers) negatively affects the nervous system, circulatory system, and can be lethally toxic in high doses. It was a whole bunch of physiology that may have gone over a few folks’ heads (I hope not). I’ll go lighter on the physiology in this article.

Some may still be saying, so what? Maybe you figure a little joint pain is just part of the game, or you went on Pubmed and found abstracts talking about the positive effects of capsaicin in studies. I’ve seen most of those studies and nearly all of them involve either isolated cell cultures, in vitro antioxidant activity, and/or are very short-term. That’s not really what I want, and I don’t think it’s what you want either. I want (human and animal) in vivo studies, epidemiological studies, and most importantly, long-term studies. Maintaining one’s health these days, as most of us who care to read the PMenu already know is a marathon and not a sprint.

An important thing to remember about the gastrointestinal tract in humans is that it extends all the way from your mouth/nose (which connect together internally) to the anus. If capsaicin is the irritant I may have led you to believe, then we could theorize that pathology (disease) could be encountered anywhere along its entire length. Let’s see what we find.

Let’s start off with a pertinent quote from this 1995 study, quite an understatement if you ask me:

“Considering the frequent consumption of capsaicin as a food additive and its current medicinal use, correct assessment of hazardous effects of this compound is important.”

Well…duh! You make the call after reading my last article and the rest of this one if the correct assessments are currently being made—13 years later! I think most readers already know my take on that one.

I’m going to let you know that the big “C” word is the subject today, as in Cancer. I figured I might as well pull out the big guns first. To begin with, in my perspective, cancer is related to failure(s) of the immune system for any number and combination of reasons. We’ll first go through animal studies, including studies involving tumors (not always cancerous, typically adenomas, always considered potentially pre-cancerous), capsaicin-induced cancers and capsaicin-promoted cancers. Here we go!

Natural Killer (NK) cells and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) are major players in the immune system as it relates to cancer processes. What happens to the immune system of neonatal rats given capsaicin?

In vivo capsaicin treatment inhibits rat NK cell cytotoxic functions.
“Capsaicin treatment resulted in a marked inhibition of NK and ADCC activities both in the spleen and peripheral blood. Inhibition was already evident on day 15 after treatment and persisted until day 90 in the spleen; at this time NK cytotoxicity in the peripheral blood returned to control levels.”

And we’re off and running! Depressed immune function in the parts of the immune system that hunt down abnormal cells that lasted for 90 days!

Let’s begin with a long-term animal study.

Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice.
“Capsaicin was administered in a semisynthetic powdered diet at 0.03125% level for the lifespan of Swiss mice starting from 6 weeks of age. As a result of capsaicin treatment, tumors of the cecum were induced in 22% of females and 14% of males, whereas the corresponding tumor incidences in untreated female and male controls were both 8%.”

That doesn’t look so good. Moving on to the short(er)-term studies.

Tumorigenicity and mutagenicity studies with capsaicin of hot peppers.
“Capsaicin, the pungent principle of hot pepper, was administered at concentrations of 1, 0.5, 0.25, 0.125 and 0.0625% in powdered diet for 35 days to five groups of Swiss albino mice. In the capsaicin-treated groups 4 mice (10%) developed 4 adenocarcinomas of the duodenum (one tumor at each dose level, except for the highest dose), while no such tumor occurred in the untreated control mice.”

The above studies were done in “healthy” lab mice. What happens when mice and/or rats are given dietary capsaicin along with or without a known tumor “promoter” (a chemical in the body, whether natural or synthetic, that aids or stimulates the growth of cancerous cells) aka procarcinogen?

Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin.
“Adenocarcinoma of the abdomen was observed in 7/20 mice fed 100 mg red chilies per day for 12 months; no tumors were seen in control animals. Neoplastic changes in the liver and intestinal tumors were observed in rats fed red chili powder at 80 mg/kg/day for 30 days, intestinal and colon tumors were seen in rats fed red chili powder and 1,2-dimethyl hydrazine, but no tumors were observed in controls…Other feeding studies evaluated the effect of red chili peppers on the incidence of stomach tumors produced by N-methyl-N'-nitro-N-nitrosoguanidine, finding that red pepper had a promoting effect.”

Co-carcinogenic effects of several Korean foods on gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.
“In study I, tumor incidence in rats fed a red pepper diet and N-methyl-N'-nitro-N-nitrosoguanidine MNNG solution were 57 per cent (ACI rats, 1 per cent red pepper) and 63 per cent (Fisher rats, 1 per cent or 3 per cent red pepper) which were higher than control group (44 per cent, 43 per cent)…Thus, gastric carcinogenesis was enhanced by red pepper and a high salt diet, was inhibited by a maejoo and ginseng diet and was not effected by vitamin A.”

Tumour-promoting effect of chilli extract in BALB/c mice.
“Using a protocol of DMN-OAc + chilli as a promoter, we observed induction of stomach tumours. The promoter effect of chilli extract was also seen in the BHC-induced hepato-carcinogenesis system. It thus appears that, in BALB/c mice, chilli acts as a promoter in stomach and liver carcinogenesis.”

Influence of red chilli on lipids and bile acids in different tissues in experimental colon cancer.
“Effect of feeding red chilli on the levels of lipids, fecal bile acids and fecal sterols was studied in animals given 1,2-dimethylhydrazine (DMH)… When the three experimental groups were compared with control…Morphological and histopathological studies show that there were a number of visible malignant tumors in the colon and intestine of all the three experimental animals.”

Effect of spices on lipid metabolism in 1,2-dimethylhydrazine-induced rat colon carcinogenesis.
“We investigated the effect of red chilli (Capsicum annum L.), cumin (Cuminum cyminum L.), and black pepper (Piper nigrum L.) on colon cancer induced in rats by a colon-specific carcinogen, 1,2-dimethylhydrazine (DMH)…Our results show that chilli supplementation promotes colon carcinogenesis, whereas cumin or black pepper suppresses colon carcinogensis in the presence of the procarcinogen DMH.”

Tumors of the stomach, liver, intestines, and colon—even though I’m not a rat or a mouse, I would absolutely take pause at those results.

Let’s move on to humans, shall we? Here we mainly have epidemiological studies. We’ll begin our tour way up in the nasopharynx of Tunisians…

Diet, living conditions and nasopharyngeal carcinoma in Tunisia—a case-control study.
We conducted a case-control study of nasopharyngeal carcinoma (NPC) in Tunisia, on diet, dietary patterns and life style, the characteristics of which had been defined by an anthropological study…After adjustment for an empirical living conditions score, the following food items were found to be associated with an increased risk for NPC: preserved spiced meat (quaddid), basic stewing preparation (mixture of red and black pepper, garlic, oil, caraway and coriander), and harissa (red pepper, olive oil, garlic, caraway, salt) taken with bread as a snack during childhood and youth.

From there, we’ll move down to the esophagus. I’ll bet nearly all of you reading this know at least one, if not several people, who get heartburn from “spicy” foods.

Gastroesophageal reflux in healthy subjects induced by two different species of chilli (Capsicum annum).
BACKGROUND: Although the ingestion of chilli has been associated with gastroesophageal reflux (GER) symptoms, there are no studies that have explored the effect of a chronic ingestion of different kinds of chilli with a variable content of capsaicin as a cause of GER…Our results suggest that the chronic ingestion of chilli induces GER, and that the magnitude of the induced reflux seems to be related to the kind of chilli.

If one doesn’t want esophageal cancer, it’s a wise idea to avoid GERD. See here and here for a bit more insight into that relationship. Moving along, down into the stomach…

Capsaicin pepper, cancer and ethnicity.
There are four cookeries in the United States that are noted for their high pepper content: Mexican-American, Cajun, white Creole, and black Creole. Each is largely confined to a single ethnic-cultural group which is concentrated in some counties. By use of county population and mortality data, significantly higher rates for stomach and liver cancer were found in counties inhabited by these four ethnic-cultural groups than in matched control counties. This involved both sexes. The cancer increase was dependent on the concentration of these groups in a county. These results strengthen and extend an earlier case-control study which found odds ratios above 5 for the stomach cancer association with capsaicin pepper. It is further evidence that capsaicin is a human carcinogen.

Diet and stomach cancer: a case-control study in South India.
A prospective case-control study was conducted in Trivandrum, India, to evaluate the dietary risk factors for stomach cancer…On multivariate analysis, high consumption of rice, high consumption of chilli and consumption of high-temperature food were found to be independent risk factors.

Capsaicin consumption, Helicobacter pylori positivity and gastric cancer in Mexico.
“The risk of gastric cancer was increased (OR = 1.71; 95% CI = 0.76-3.88) among high-level consumers of capsaicin (90-250 mg of capsaicin per day, approximately 9-25 jalapeño peppers per day) as compared to low-level consumers (0-29.9 mg of capsaicin per day, approximately 0 to less than 3 jalapeño peppers per day; p for trend p = 0.026); this effect was independent of Helicobacter pylori status and other potential GC determinants…Chili pepper consumption might be an independent determinant of GC in Mexico.”

Chili pepper consumption and gastric cancer in Mexico: a case-control study.
A population-based case-control study was conducted in Mexico City during 1989-1990 to evaluate the relation between chili pepper consumption and gastric cancer risk…Chili pepper consumers were at high risk for gastric cancer compared with nonconsumers. Among consumers, there was a highly significant trend of increasing risk with increasing self-rated level of consumption (low, medium, and high). The odds ratio for high-level consumers compared with nonconsumers was 17.11.

Now, I’m not a statistician. That being said, the final study showing that self-rated high-level consumers of chili peppers have a 17+ times greater risk of contracting gastric cancer is absolutely frightening.

Most people who eat peppers love to combine them with meat. That may not be the best idea, as apparently it inhibits iron absorption.

Chili, but not turmeric, inhibits iron absorption in young women from an iron-fortified composite meal.
“Addition of freeze-dried chili (4.2 g dry powder, 25 mg polyphenols as gallic acid equivalents) reduced Fe absorption from the meal by 38% (6.0% with chili vs. 9.7% without chili, P = 0.0017).”

In human bowels, pepper and capsaicin consumption have been consistently observed to decrease bowel transit time (1, 2) and increase bowel movement frequency. While some would have you believe that this is inherently a good thing, I disagree based on what I know of capsaicin as an irritant. My assumption is that the body wishes to clear itself of the irritating compounds as quickly as possible.

On to the gall bladder, starting off with a potential mechanism related to substance P again. For more on this capsaicin-dependent mechanism, see last month’s nightshade article.

Changes of the different neuropeptide containing nerve elements in the inflamed human gall bladder.
The changes of different neuropeptide containing nerve elements might play a role in the pathogenesis of cholecystitis and the formation of gallstones, therefore the authors have investigated the density of the neuropeptide containing nerve fibers and immunocompetent cells in human gallbladder (control and cholecystitis). In the inflamed gallbladder…the number of the substance P (SP) immunoreactive (IR) nerve fibers was decreased significantly in the cholecystitis. In the inflamed area the number of immunocompetent cells was strongly increased (being granulocytes, lymphocytes, plasma cells and mast cells) and some of them were also immunoreactive for SP, calcitonin gene-related peptide (CGRP) and VIP.

Quick refresher on substance P: capsaicin administration depletes and/or downregulates the SP nerve endings of it, and a lack of SP in an area inhibits (or halts) proper healing. So, the above study of inflamed gall bladders demonstrates a reduction in substance P nerve fibers in the gall bladder. Not a good sign for healing, but what about cancer?

Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population.
Multivariate analysis kept only a very low socioeconomic status and red chili pepper consumption as significant independent risk factors for gallbladder cancer, odds ratios of 6.3 (95% CI 1.7-23.0) and 3.2 (95% CI 1.7-5.9).

Yet another study that mentions pepper consumption as an independent risk for cancer. Moving down into the colon, we have another study that implicates capsaicin, substance P, and TRPV1 receptors (also discussed thoroughly in last month’s article) as having significant roles in inflammatory bowel disease and tumor/cancer formation. In my previous article, research was presented that TRPV1 receptor “knockout” mice (bred to not have that receptor, a receptor that is stimulated by capsaicin) were nearly immune to adjuvant-induced arthritis and capsaicin-induced articular (joint) vasoconstriction. A TRPV1 receptor antagonist reduced pain in several types of animal models. The following study shows that the administration of substance P helps facilitate healing from colitis.

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation.
“We examined the hypothesis that substance P (SP) and the neurokinin-1 receptor (NK-1R), both in vitro and in vivo, promote mucosal healing during recovery from colitis by stimulating antiapoptotic pathways in human colonic epithelial cells…Thus, SP, through NK-1R, possesses antiapoptotic effects in the colonic mucosa by activating Akt, which prevents apoptosis and mediates tissue recovery during colitis.”

Immunohistochemical distribution of vanilloid receptor, calcitonin-gene related peptide and substance P in gastrointestinal mucosa of patients with different gastrointestinal disorders.
The immunohistochemical distribution of capsaicin/vanilloid (transient receptor potential vanilloid 1, TRPV1) receptors and neuropeptides (CGRP, SP) was studied in the gastrointestinal mucosal biopsies of patients with gastritis, erosions, ulcers, polyps, adenocarcinoma, chronic inflammatory bowel diseases, polyps without and with hyperplasia, dysplasia and adenocarcinoma in colon. The results were: (1) the positivity of TRPV1 receptor and CGRP was detected, and weak participation of SP was detected in patients with different gastric diseases; (2) the presence of TRPV1, CGRP and SP could be detected in chronic inflammation of bowel disease; (3) SP could not detected in patients with colon polyps, dysplasia and adenocarcinoma; (4) the presence of TRPV1 and CGRP was proved in colon dysplasia and adenocarcinoma.

In the final study above, several important things come up, which I will address with the same numbers the study’s authors used:

1. TRPV1 receptors were present in the GI mucosa of those with gastrointestinal disorders, potentially making those tissues susceptible to similar inflammatory mechanisms as the rat arthritis models in my last article. “Weak” participation could be interpreted as previous overstimulation of the SP nerve endings by capsaicin, most likely through dietary habits, thus resulting in the typical SP nerve ending downregulation/degradation pattern and associated low levels of SP present.
2. When subjects were still dealing with chronic inflammatory bowel disease, there was still some SP around, as opposed to…
3. Once the disease process(-es) had progressed to dysplasia, polyps, or cancer, there was no SP left to be found. That means little to no healing would take place in those areas.
4. TRPV1 receptors were found in the dysplastic and cancerous cells, meaning they are potentially receptive to continued inflammatory stimulus from capsaicin.

Those last two points could account for the aggressiveness of GI tract cancers in general when people don’t make the proper changes to their diet. No SP, no healing—stimulate TRPV1, stimulate inflammatory processes and possibly vasoconstriction.

In conclusion…if you want to take a step towards avoiding cancer of your digestive tract, I’d highly suggest you stay far away from peppers!