Capsaicin has been revealed to inhibit lipid peroxidation in red blood cell membranes as well as in the liver and mitochondria of mice, and it can block the peroxidation of low-density lipoproteins in humans (10,11). In fact, the antioxidant activity of capsaicin exceeds that of vitamin E in some cases (12). The levels of capsaicin in food can alleviate oxidative stress and increase cellular antioxidant capacity by preventing reactive oxygen species from oxidizing glutathione (13). Capsaicin can reverse the ability of high blood cholesterol levels to inhibit the antioxidant enzymes glutathione reductase, glutathione transferase and superoxide dismutase (14,15). Capsaicin can also scavenge free radicals such as 1,1′-diphenyl-2-picrylhydrazyl (DPPH) (13). Other members of the capsaicin family, such as dihydrocapsaicin and 9-hydroxycapsaicin, appear to have antioxidant activity similar to that of capsaicin (16).

In capsaicin and other members of the family, the benzene ring and the substituents of the benzene ring appear to be important for antioxidant activity. The benzene ring of capsaicin may interact with the benzene ring of DPPH, while the methoxy and hydroxy substituents at the ortho position of the benzene ring can strongly influence antioxidant activity (13).

Adults who received capsaicin for 4 weeks demonstrated lower levels of oxidation of serum lipoproteins (17). In mitochondria, capsaicin can reduce lipid peroxidation and, more generally, oxidative stress. It can alleviate ischemia-reperfusion injury in myocardium and kidney. Most of these antioxidant effects appear to be mediated by TRPV1 (18). The search continues for capsaicin analogues with even stronger antioxidant activity.

TRPV1 is a Ca²⁺-selective member of the family of transient release potential ion channels, which sense heat. TRPV1 in the prelimbic and infralimbic cortex has also been revealed to mediate neuropathic pain. TRPV1 is broadly distributed in tissues of the brain, bladder, kidneys, intestines, epidermal keratinocytes, glial cells, liver, polymorphonuclear granulocytes, mast cells and macrophages (19).

Capsaicin is an agonist of TRPV1 that reduces its activation threshold. Uniquely, after TRPV1 has been activated by capsaicin, the receptor enters a long-lasting refractory state, in which it does not respond to mechanical pressure, pain or inflammatory agents (20). This so-called ‘defunctionalization’ results from the closing of the channel pore due to conformational changes that depend on extracellular Ca²⁺. To what extent this transient ‘defunctionalization’ explains the observed analgesic effects of capsaicin remains unclear (21).

When activated by capsaicin, TRPV1 mediates Ca²⁺ influx and glutamate release, which may damage cutaneous autonomic nerve fibers and sensory nerve endings, decreasing pain sensation. In adult rats, the capsaicin analogue resiniferatoxin damages TRPV1-expressing myelinated nerve fibers and eliminates TRPV1-expressing unmyelinated nerve fibers, reducing perception of thermal pain.

The US Food and Drug Administration has approved capsaicin as an 8% dermal analgesic patch (640 mcg/cm², total dose 179 mg), while lower doses do not relieve pain effectively (22). The 8% patch has proven safe and effective in controlling neuropathic pain resulting from post-herpetic neuralgia, post-surgical neuralgia, post-traumatic neuropathy, polyneuropathy and mixed pain syndrome (23). In a previous trial (24), capsaicin markedly reduced pain attacks, prolonged sleep duration and improved sleep quality, while reducing dependence on opioids and antiepileptics. ~10% of patients in that trial reported adverse drug reactions, the most frequent of which were erythema and pain at the application site. In a different study including two clinical trials, it has been suggested that the 8% patch is effective against HIV-associated distal sensory polyneuropathy (25).

Adlea, a highly purified form of capsaicin, has exhibited analgesic efficacy in clinical trials involving patients with intermetatarsal neuromas, lateral epicondylitis or end-stage osteoarthritis. A trial is ongoing to assess the safety and efficacy of the drug for patients undergoing total knee arthroplasty (23,26).

N-palmitoyl-vanillamide, also called palvanil, is also present in Capsicum but at markedly lower levels than capsaicin. Palvanil has demonstrated analgesic potential while inducing smaller fluctuations in body temperature and bronchoconstriction than capsaicin. It also exerts the analgesic effects through TRPV1, activating the receptor more slowly and defunctionalizing it more completely than capsaicin does (27).

Similar to numerous other dietary phytochemicals, capsaicin shows antitumor activity. It alters the expression of several genes that arrest the cell cycle in tumor cells and promotes apoptosis. These effects have been demonstrated in colon adenocarcinoma, pancreatic cancer, hepatocellular carcinoma, prostate cancer, breast cancer and numerous other types of cancer (Table I), without damage to normal cells. The way capsaicin exerts these effects is only beginning to emerge and the mechanisms appear to involve accumulation of intracellular Ca²⁺, generation of reactive oxygen species, disruption of mitochondrial membrane potential and upregulation of the transcription factors NF-κB and STATS. Capsaicin has been revealed to act through TRPV1 to promote apoptosis of numerous types of cancers. Whether it also acts through other TRPVs, such as TRPV6 in prostate cancer, remains to be clarified (28,29).

Capsaicin causes TRPV1 to stimulate the release of catecholamine from catecholaminergic neurons in the rostral ventrolateral medulla of the brain, thereby promoting weight loss (30). It upregulates adiponectin and other adipokines to reduce fat accumulation in obese mice. Capsaicin has been shown to decrease appetite (31). When delivered as part of a high-fat diet, it increases thermogenesis and lipid oxidation, while also reducing levels of fasting glucose and plasma triglycerides, which suggests therapeutic potential for obesity-related diseases such as insulin resistance and type 2 diabetes mellitus (32,33). Indeed, studies of various capsaicin doses in obese mice have suggested that it can partially reverse obesity-induced glucose intolerance by suppressing inflammatory responses and enhancing fatty acid oxidation in adipose tissue and liver (34).

On the other hand, certain studies (35,36) have failed to detect any effect of capsaicin on energy expenditure or lipid oxidation. While the absence of these effects may be real, it may also be an artifact of administering too little capsaicin for a short period of time, or the thermogenic effects may be too subtle to detect in the relatively small animal groups and short measurement periods in those studies.

The available evidence suggests that capsaicin lowers lipid levels by altering intestinal permeability and the gut microbiome, in turn influencing the gut-brain axis (37) (Fig. 3). Future studies are needed to verify and elucidate the molecular pathways involved.

In rats and guinea pigs, TRPV1 is expressed and active within the myenteric ganglia and inter-ganglionic fiber tracts that extend throughout the gastrointestinal tract, including the muscle layers, blood vessels and mucosa within the tract (38). TRPV1 is also expressed outside the gastrointestinal nervous system, such as in gastric epithelial cells, in which it stimulates the secretion of gastrin (39).

Previous studies have attributed several positive gastrointestinal effects to capsaicin: It induces the release of calcitonin gene-related peptide, activates gastroprotective cyclooxygenase-1 and increases the absorptive surface of the small intestine by lengthening and thickening microvilli and by altering the permeability of the brush border membrane, in turn increasing zinc absorption (40–42). In non-alcoholic fatty liver disease, dietary capsaicin has been revealed to promote hepatic phosphorylated hormone-sensitive lipase, carnitine palmitoyltransferase 1 and peroxisome proliferator-activated receptor δ (43).

On the other hand, a number of studies have suggested that prolonged exposure to high doses of capsaicin can harm the gastrointestinal tract. Thus, exploring the minimum effective doses required to achieve the desired therapeutic effects and minimizing the potential side effects are quite necessary for enhancing the clinical utility of capsaicin-based treatments. TRPV1 activation induces release of substance P, which can drive gastrointestinal inflammation (44). In addition, TRPV1 is upregulated in irritable bowel syndrome and appears to contribute to the gastrointestinal hypersensitivity and pain associated with the condition (22,45).

Capsaicin has demonstrated therapeutic potential in several animal models of Alzheimer's disease (AD). It can partially reverse streptozotocin-induced biochemical and behavioral changes that mimic AD (46). In the APP/PS1 mouse model, capsaicin reduced the formation of amyloid fibrils from amyloid precursor protein. In a third AD model (47), capsaicin substantially ameliorated synaptic damage and tau hyperphosphorylation induced by cold water stress. Further studies should explore the therapeutic potential of dietary capsaicin for treating and possibly even preventing AD (48).

In an animal model of Parkinson's disease based on lipopolysaccharide-induced inflammation, capsaicin appeared to activate TRPV1 in M1/M2 dopaminergic neurons, which may alleviate neuro-inflammation and oxidative stress from activated glia (49). The beneficial effects of capsaicin and TRPV1 were confirmed in these studies using appropriate antagonists (50). Future studies should continue to explore the potential of capsaicin for treating Parkinson's disease and should elucidate the mechanisms involved.

TRPV1 is expressed in human keratinocytes. Although activation of epidermal TRPV1 induces the release of inflammatory factors, capsaicin downregulates hypoxia-inducible factor-1α in psoriatic epidermis, slowing epidermal proliferation (51). It also mitigates itching mediated by histamine, substance P and proteinase activated receptor-2. On the other hand, previous studies have failed to detect therapeutic effects of capsaicin against hemodialysis-induced pruritis, idiopathic intractable pruritis and notalgia paresthetica (52,53). In fact, an animal study linked capsaicin to the development of chronically relapsing pruritic dermatitis, which was associated with an elevated number of mast cells and hyperproduction of immunoglobulin E (54,55).

TRPV1 is expressed in the sensory nerves in cardiovascular structures, near the epicardium and in vascular endothelial cells (56). When blood flow to myocardium is reduced, such as during myocardial infarction, free oxygen radicals are produced, which activate TRPV1 (57). Myocardial injury also upregulates 12-hydroperoxyeicosatetraenoic acid, a metabolite of 12-lipooxygenase arachidonic acid that may bind to TRPV1 (58). Activation of the receptor may exert cardio-protective effects, leading to smaller infarcts and milder ischemic/reperfusion injury (59).

TRPV1 in the vasculature can promote vasoconstriction or vasodilation, depending on the situation. In the case of vasoconstriction, TRPV1 activation results in the release of substance P, which binds to neurokinin 1 (60,61). In the case of vasodilation, TRPV1 activation results in the release of calcitonin gene-related peptide or of protein kinase A and nitric oxide synthase (62,63). In both cases, TRPV1 activation leads to an increase in intracellular Ca²⁺ (64,65).

Capsaicin inhibits platelet aggregation, potentially by altering the fluidity of the platelet membrane. This mechanism appears to be independent of TRPV1 because the effects are not inhibited by a competitive TRPV1 inhibitor. On the other hand, capsaicin has also been shown to promote platelet aggregation through a mechanism dependent on TRPV1 (66–69). In that mechanism, TRPV1 may induce release of serotonin to drive platelet activation in response to adenosine diphosphate and thrombin (70–74).