Capsaicin: Emerging Pharmacological and Therapeutic Insights.

This review was conducted by systematically searching major electronic databases, including PubMed, Scopus, and Web of Science. The search strategy was developed using a combination of Medical Subject Headings (MeSH) and keywords. MeSH terms included “Capsaicin”, “Biochemical Properties”, “Therapeutic Applications”, and “Pharmacology”. Keywords related to these terms, such as “pain management”, “analgesic effect”, and “TRPV1 receptor”, were also used to ensure comprehensive coverage. Inclusion Criteria: Peer-reviewed articles and studies focused on the biochemical properties, therapeutic applications, or pharmacological insights of capsaicin. Exclusion Criteria: Studies not specifically addressing capsaicin, non-peer-reviewed literature, such as abstracts, conference proceedings, and grey literature. The search strategy aimed to capture a wide array of relevant studies to provide an updated and comprehensive overview of capsaicin. Each database was searched using tailored strategies to maximise the retrieval of pertinent studies. The selection process involved screening titles and abstracts, followed by a full-text review to ascertain eligibility based on the predefined inclusion and exclusion criteria.

Being liposoluble, capsaicin is well absorbed orally, as well as at the digestive tract level; internal administration means that it will also reach systemic circulation, while systemic administration itself is also possible [ 76 ]. The absorption of capsaicin takes place at the level of the stomach and the intestine, varying between 50% and 90%; at any rate, it is invariably a passive process [ 77 ]. The intestinal epithelial cells can metabolise a small percentage of the absorbed capsaicin [ 78 ]. Despite its lipophilicity, which correlates with good skin absorption [ 79 ], capsaicin does not reach sufficiently high levels in the plasma following local or transdermal administration to exert its effects systemically [ 80 ]. Following its internal (oral) administration, capsaicin is hepatically metabolised [ 78 ], with the small aforementioned exception. Based on in vitro studies, it has been established that, following its rapid metabolisation, the three most important metabolites are 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin; vanillin is a minor metabolite [ 81 , 82 ]. Based on a subsequent study [ 83 ], another metabolite of capsaicin was identified, which corresponds to a compound occurring after phase I demethylation and dehydrogenation. A glycine and a glutathione conjugate were also identified. At any rate, a small percentage of capsaicin is fecally excreted, while most of the elimination is renal for the glucuronide metabolites of capsaicin [ 84 ]. While it may be assumed that cytochrome P 450 enzymes are, most probably, involved in capsaicin metabolism [ 85 , 86 ], in human skin cell studies, the biotransformation process has been found to be slow, and most of the administered capsaicin did not undergo any changes [ 87 ]—this last fact has important implications for medicinal capsaicin applications. The half-life of capsaicin in the human body was determined to be 25 min [ 87 ]; conversely, the local application of a 3% capsaicin solution yielded a value of 24 h [ 88 , 89 ]. More recent research [ 90 ] has identified a novel metabolic pathway in the human body, resulting in macrocyclic diene and imide metabolites. The first physiological action of capsaicin is observed when it binds to the TRPV1 (transient receptor potential cation channel subfamily V member 1) [ 91 ]; capsaicin is a potent TRPV1 receptor agonist [ 92 ]. Such is the physiological importance of this receptor, and of temperature and mechanically activated channels in general, that research on them resulted in the awarding of the 2021 Nobel Prize in Physiology or Medicine to David Julius and Ardem Patapoutian [ 93 , 94 , 95 ] based on their previous research (e.g., [ 96 , 97 , 98 , 99 , 100 , 101 ]). This receptor, which is also called capsaicin or vanilloid receptor 1 [ 102 ], can be activated, apart from its agonists, by a temperature higher than 43 °C and a pH lower than 5.2. Some examples of endogenous agonists are bradykinin and prostaglandins [ 103 ]. The receptor function is associated either with protein kinase A or protein kinase C [ 104 , 105 ]. The activation of this receptor enables it to exert its modulatory activity; its principal role is body temperature regulation [ 106 , 107 ]. The heat perception properties of TRPV1 have also been proposed by Tominaga et al. [ 108 ] who have also noted that TRPV1 is instrumental in peripheral nociception. The nerve signals resulting from its activation reach all up to the spinal cord and eventually the brain. TRPV1 was identified in the central nervous system as well as in the sensory neurons of the dorsal root ganglion [ 109 ]. At the level of the cardiovascular system, it can also be found in vascular smooth muscle cells and endothelial cells [ 110 ]; of course, neural TRPV1 activation will also have cardiovascular-related effects [ 111 ]. It must be noted that TRPV1 does not seem to be expressed in cardiomyocytes [ 112 ], but there is a report indicating that it is possibly expressed in the nerve fibres of the epicardium [ 113 ]. At the level of the respiratory system, TRPV1 is found in the airway epithelial cells and in the T cells of the upper and lower airways [ 114 ]; interestingly, the expression of TRPV1 in the respiratory system seems to vary in different pathological situations [ 115 , 116 ]. At the level of the gastrointestinal tract (GIT), TRPV1 can be found in the submucosal nerve plexus, myenteric nerve plexus, gastrointestinal mucosal cells, parietal and antral G cells [ 117 ]. At the level of the integumentary system, TRPV1 can be found in a number of different cell types, namely unmyelinated type C and thin myelinated A δ sensory nerve fibres, keratinocytes, sebocytes, dermal blood vessels, mast cells, fibroblasts, hair follicles, and vascular smooth muscle cells [ 118 , 119 , 120 ]. In the eyes, TRPV1 is present in corneal cells [ 121 ] and retinal ganglion cells [ 122 ]. Capsaicin induces a variety of TRPV1-mediated sensations with different intensities, from warming and tingling up to burning [ 123 , 124 ]. Another aspect that must be considered is that capsaicin-induced activation of TRPV1 is more persistent compared to the effect of other natural agonists. In fact, capsaicin is a more potent agonist compared to any endogenous TRPV1 agonists—which have been analysed in detail in recent studies [ 125 ]—and, although being the most characteristic exogenous TRPV1 agonist [ 126 ], there are some more potent such agonists, like resiniferatoxin [ 127 , 128 ] and a number of recently researched compounds [ 129 ]. The capsaicin-induced activation of TRPV1 is associated, at least in a number of cases, with a relative desensitisation [ 130 ]. Capsaicin exerts a host of different effects at cellular [ 131 , 132 , 133 , 134 , 135 ] and subcellular levels [ 136 , 137 ]. Two pathways are thought to exist via which capsaicin may inhibit nociception: a TRPV1-dependent one and a TRPV1-independent one. The TRPV1-independent effects are associated with changes in the lipid membrane properties, the modulation of voltage-gated ion channels and direct binding to other enzymes and transporters [ 138 , 139 , 140 ]. The TRPV-1-dependent pathway implies activation of the receptor and subsequent desensitisation, which can be modulated by various factors, including cAMP/PKA-dependent activation [ 141 , 142 ]. Both the dependent and independent effects are most possibly associated with the reduced nociception caused by capsaicin [ 138 ]. The aforementioned blockade of nociceptors, when coupled with the capacity of reducing the inflammation-associated substance P [ 143 ], renders capsaicin a good candidate for a non-narcotic analgesic [ 144 , 145 ]; indeed, the new technologies available render the design of pharmacological capsaicin analogues a possible and potent eventuality [ 126 ]. In the manifestation of analgesic effects, the indirect blockage of voltage-gated Na + channels may also play a role [ 146 , 147 ]. In addition, some other associated capsaicin-induced actions comprise the degeneration of epidermal nerve fibres after prolonged local administration [ 148 ]. A number of researchers have presented the most recent developments regarding the novel analgesic capsaicin applications [ 149 , 150 , 151 , 152 ]. A general outline of the TRPV1-mediated activation by capsaicin is presented in Figure 1 .

In general, the uses of capsaicin are numerous and varied, ranging from medicine, either human or veterinary, to uses in agriculture, the food industry, and fragrances. In human medicine, we distinguish between local and systemic applications ( Table 2 and Table 3 ). As discussed above, capsaicin is lipophilic and can hence be absorbed readily, reaching and activating the TRPV1 receptor, which can be found both in nociceptive and non-nociceptive structures. The binding of capsaicin leads to receptor activation, upon which a prolonged desensitisation state prevails; this second state renders the use of capsaicin very promising in chronic pain syndromes, as well as against hyperplasias, inflammation and inflammatory skin diseases, various dermatoses, as well as chemotherapy-induced and radiotherapy-induced mucositis [ 153 ]. For local applications, a variety of capsaicin preparations are available, such as creams, gels, liquids and patches [ 154 ], while novel formulations comprise nanolipid carriers [ 155 , 156 , 157 ], flexible membrane vesicles [ 158 ] and alginate microcapsules [ 159 ]. These last formulations can be considered better in that they improve the pain threshold in a dose-dependent manner, compared to the older locally-administered drugs; the positive effect is exerted through the reduction of tissue prostaglandin E2 levels, while skin irritation is also reduced [ 160 ]. The most prominent local capsaicin applications are presented in Table 2 . Local applications of capsaicin. Most, if not all, of the local applications mentioned in Table 2 can be combined with anti-inflammatory drugs; this enables augmentation of their effects, thus leading to dose reduction, which diminishes their systemic side effects [ 230 ]. It may be observed that an abundance of these applications is associated with the inhibition and/or depletion of substance P; substance P, a bioactive peptide of the tachykinin family [ 231 ], is secreted by nerve cells and a host of inflammatory cells [ 232 ]. Substance P is associated with neurogenic inflammation [ 233 , 234 ] both systemically and at the level of the skin [ 235 , 236 , 237 ], the cardiovascular system [ 238 , 239 ], the respiratory [ 240 , 241 , 242 ], gastrointestinal [ 243 , 244 , 245 ] and genitourinary [ 246 , 247 ] tracts and also in the cerebral arteries [ 248 , 249 ]. The relative ubiquity of substance P in the human body renders it a prime target for pharmacological interventions in inflammatory diseases [ 250 ]. Notably, substance P is associated with infection-induced inflammation, a fact proven in both human and animal models [ 251 , 252 , 253 , 254 ]; taking into account the already proven antimicrobial properties of capsaicin, this could prove an interesting research avenue. In an experimental setting, capsaicin has also been used locally to demonstrate the effects of psychological triggers on vascular responses [ 255 ]—this could be a useful future experimental avenue. In the recent relevant literature, the tissue-specific and systemic side effects of capsaicin have been rigorously studied. Despite its lipophilicity, local capsaicin administration does not result in any systemic bioavailability, a fact correlating with its poor aqueous solubility properties [ 256 ]. Here, it must be remarked again that systemic capsaicin administration correlates with a number of dose-dependent side effects [ 257 ]. Since most of these effects are usually GIT-related, they can now be mostly obviated by employing liposomal carriers, which release capsaicin directly into the blood flow [ 258 , 259 ]. In Table 3 , based on selected scientific publications, the most notable systemic effects of capsaicin are presented. Systemic effects of capsaicin. In addition to all the aforementioned, in a recent experimental study, it was shown that capsaicin inhibits a series of proteins associated with the Warburg effect in sepsis and also downregulates cyclo-oxygenase 2 (COX-2) in a TRPV-1-independent manner [ 277 ]. This is important for a number of reasons; to start with, the Warburg effect, originally proposed in the 1920s [ 278 , 279 ], is essential for the metabolism of cancer cells [ 280 ], and its inhibition might provide an avenue for novel therapeutic strategies [ 268 , 281 , 282 ]. Secondly, the inhibition of COX-2, which is already the target of a number of drugs (e.g., [ 283 , 284 , 285 ]), means that capsaicin can be used in conjunction with them to enhance their effect. Finally, in the presence of TRPV-1 agonists other than capsaicin (e.g., [ 286 , 287 , 288 ]) or antagonists (e.g., [ 289 , 290 , 291 , 292 ]), this approach will, theoretically, still be functional. The anticarcinogenic effect of capsaicin is mainly associated with the activation of TRPV1, which can be considered a probable link between inflammatory, immune and carcinogenic processes, as seen in Table 4 . There are several events in the anti-cancer trajectory of capsaicin that were documented: antimutagenic activity, anti-oxidative action, anti-inflammatory action, cell cycle regulation and clear involvement in cancer cell death [ 328 ]. Out of all the mentioned molecular events associated with capsaicin’s anti-cancer action, the induction of cancer cell death is the most important, as capsaicin acts on multiple targets. As outlined in Figure 2 , besides TRPV1, another member of the TRPV family involved in the anti-cancer action of capsaicin is TRPV6. Comparable to TRPV1, TRPV6 regulates calcium homeostasis. In in vitro studies, it was shown that capsaicin increases TRPV6 expression and increased levels of intracellular calcium ions that activate the calpain pathway for apoptosis [ 329 ]. Moreover, TRPV6 overexpression increased mitochondria permeability through the activation of Bax and p53 through C-jun N-terminal kinase (JNK) activation. Apoptosis can thus be induced by capsaicin in a TRPV1-dependent and independent manner. In the TRPV1 independent pathway, capsaicin activates adenosine 5-monophosphate-activated protein kinase (AMPK), p53 and JNK. When capsaicin binds to the mitochondrial complex I and II in the electron transport chain, the mitochondrial membrane potential is disrupted, and the membrane permeability is increased. Capsaicin increases ROS levels and increases the expression of pro-apoptotic Bcl-2 (Bax), as it was found in the case of neuroendocrine melanoma, a very aggressive and fatal tumour by Jun et al. [ 294 , 330 , 331 ]. This decreases the anti-apoptotic Bcl-2 and CytC release and induces apoptosis [ 317 ]. Some other anticarcinogenic applications of capsaicin should be mentioned here. It is possible to use capsaicin as a radio-sensitising agent in patients with prostate cancer; this particular use takes advantage of capsaicin-induced inhibition of NFκB signalling [ 332 ], resulting in angiogenesis inhibition [ 333 ]. More generally, recent studies explore the potential of combining capsaicin with conventional chemotherapeutic agents [ 334 , 335 , 336 , 337 ]. Other carcinogenesis-related signalling pathways may represent potential targets for future studies [ 338 ]. Another aspect we should consider is the increase of serum somatostatin induced by systemic capsaicin administration, which has already been noted by Thán et al. [ 260 ] and Szolcsányi et al. [ 339 ]. The release of somatostatin is associated with anti-inflammatory [ 340 ] and anti-nociceptive effects [ 341 ] in rats. The research of [ 342 ] has also focused on the somatostatin-induced inhibition of inflammation and nociception. It is known that somatostatin is linked with such effects in humans [ 342 , 343 ], and somatostatin and its analogues have already been explored as targets for anti-cancer therapies [ 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 ]. The use of capsaicin in such a manner appears to be a promising avenue in cancer therapy research—a particular application could be in the case of hepatocellular cell carcinoma (HCC) where somatostatin and capsaicin application could be, in theory, effectively combined—the application of capsaicin in the pathogenesis of HCC specifically is explored by Scheau et al. [ 124 ]. The anticarcinogenic activity of capsaicin has also been a subject of in vivo studies, where chronic exposure to capsaicin seems to actually promote neoplasia by increasing collagen and elastin deposition [ 354 ] and by inhibiting NK cell function [ 355 ]. Capsaicin also exhibits a carcinogenic potential when combined with 9, 10-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate [ 356 ]. Finally, long-term capsaicin consumption favours metastasis because it modifies the microbiome of the gut, thus promoting the translocation of bacteria to the liver and altering bile acid metabolism, which ultimately inhibits NK cell function [ 357 ]; therefore, it must be examined in detail if and under which circumstances, the use of capsaicin may actually have detrimental effects in human health.

Originally, the capsaicin-containing plants of the genus Capsicum were native to Central and South America [ 358 , 359 ]. However, after the discovery of the Americas in the 16th century, it was quickly exported, as already mentioned, and gradually became a staple of many different culinary traditions [ 360 ]. While this genus comprises about 25 species, only five of them have been domesticated [ 361 , 362 , 363 ] and are commonly cultivated [ 364 ]; although the species is typically a perennial plant, it can be cultivated as an annual crop in areas with low temperatures [ 365 , 366 ]. Chile peppers, along with a number of other parts, were integral in the Mesoamerican civilisation’s agriculture [ 367 ] and even later in the formation of traditional Mexican cuisine [ 368 ]—the same has happened in a number of other localities, such as Pueblo in Colorado [ 369 ]. The traditional medical and even culinary usage of chilli peppers, and therefore capsaicin, is quite diverse [ 370 ]. While the domestication of the plant is estimated to have taken place somewhen before the 5th millennium BC [ 366 ], it may be assumed that they were also consumed sometime before [ 371 ] since the agriculture of many pre-colonial communities was pretty advanced ([ 372 ]; and references therein); the domestication process seems to have begun independently in a number of different areas [ 358 ]. Its significance is readily apparent from archaeological finds of the pre-Ceramic (ca. 9500–900 BC) and Formative (900 BC–250 AD) periods in South America [ 373 , 374 ] (time frames based on Lanning [ 375 ]). The millennia of chilli consumption must have given rise to a number of medicinal applications. In addition, a number of different civilisations that occupied pre-Columbian America, such as the Incas [ 376 ], Mayas [ 377 ], and Aztecs [ 378 ], used chilli peppers as war-related artefacts and for ritualistic purposes [ 6 ]. While these last two uses of chilli may be seen as atypical, on the one hand, it must be remarked that the absence of a monetary economy led to natural goods and materials having a more prominent role, a typical example being that of obsidian and other rocks and minerals [ 379 , 380 ]; on the other, a significant number of civilisations have used plants in ritualistic purposes [ 381 , 382 , 383 ]. It is known that capsaicin content differs between different Capsicum species [ 384 ]. Different foodstuffs also have, as expected, differing capsaicin contents [ 385 ], and this presumably influences their various uses to some extent. In fact, it is even possible to conceive the use of chilli peppers as a food-medicine continuum in the minds of the locals [ 386 , 387 ]. Perhaps the most diverse uses are recorded in Mexico, where chile is native, as is seen in Table 5 ; interestingly, the increased capsaicin consumption in parts of Mexico seems to correlate positively with adiposity and fat markers [ 388 ]. The complete spectrum of the local ethnobotanical use of chilli peppers is provided in a recent study [ 387 ]; various uses of different parts of the chilli plants are provided by Meghvansi et al. [ 389 ]. Miscellaneous or unverified uses of peppers, and thus capsaicin, also exist, such as those reported by Saleh et al. [ 390 ]. In addition, chilli is used along with other herbs and plants for a number of diseases or ailments related to the metaphysical concept of soul and evil energy [ 397 , 403 , 406 , 409 , 410 , 411 ]. It is possible that a number of medical applications of chilli peppers in traditional medical practice, especially for Native Americans, have been lost to time or have not yet been discovered. It must not be forgotten that Inca medicine, for example, was relatively advanced and possibly superior to contemporary European practises in some fields like surgery [ 412 , 413 ], as evidenced by a variety of findings and mentions in Spanish chronicles [ 414 ]. It is, therefore, entirely possible that a number of useful and effective applications of chilli extracts, as well as those of other plants, existed. In order to elucidate the full extent of the intertwining of food, medicine and culture in a local and traditional context, further research and novel practices are required [ 415 , 416 ]. On another note, we would like to point out that, as presented in the tables of the previous sections, based on previous research [ 63 , 64 , 65 ], capsaicin cream was applied to acupuncture point P6 or K-D2, which is the Korean equivalent, and also in LI4 [ 197 ] and ST36 [ 194 ]. Most, if not all, of the effects in these cases, are associated with some form of inhibition of the synthesis, transport and/or action of substance P; indeed, substance P is integral in the modern interpretation of the action of acupuncture in many pain states [ 417 ]. Traditional Chinese Medicine (TCM) is one of the most widely used traditional medicine systems in the world, and although it does not incorporate capsaicin-containing plants in its original, ancient phytochemical tradition [ 418 , 419 ], it is interesting to note this, apparently, as of yet, successful combination with capsaicin.

Extensive research has revealed a variety of physiological and pathological effects of capsaicin ( Table 6 ); most but not all of capsaicin’s side effects are exerted by the activation of TRPV1. When applied locally, at the level of the skin or other external mucous membranes, it will induce skin erythema, neurogenic inflammation [ 420 ], non-blistering associated burning [ 421 ], marked lacrimation, blepharospasm and even conjunctivitis [ 422 ]. It must be noted here that a specific form of contact dermatitis, the so-called “Hunan hand” was first diagnosed in individuals who handled peppers daily due to their occupation. This is considered a clear and reliable marker of dermal capsaicin toxicity [ 423 , 424 ]. At the level of the CNS, capsaicin toxicity is associated with convulsions, excitement [ 425 , 426 ], disorientation and fear [ 427 ]; a host of other generalised symptoms, such as loss of body motor control, including diminished hand-eye coordination, have been reported [ 427 ]. In the cardiovascular system, capsaicin causes blood pressure increase and heart rate increase, and, in highly toxic levels, these effects may progress respectively to hypertension and tachycardia, with even ventricular fibrillation having been reported [ 427 ]. The blood pressure increase is associated both with the heart rate elevation and with the increased vascular contractility [ 428 ], leading to vasoconstriction. A summary of all the hypotheses and determined effects and side effects of capsaicin in the cardiovascular system in different modes of application has been provided in recent research [ 111 ]. Particular features of the cardiovascular system might predispose to or aggravate these responses [ 429 , 430 , 431 , 432 ]. At the level of the respiratory system, it causes bronchoconstriction and coughing [ 433 ], while in increased doses, it may even cause oedema of the larynx and the lungs, chemical pneumonitis and even respiratory arrest [ 434 ]; these data for capsaicin toxicity are derived from in vitro experiments with capsaicin analogues [ 434 ]. Systemic capsaicin toxicity has also been associated with pulmonary oedema and hyperventilation. A particular mechanism of neurogenic toxicity may be beneficial in controlling the neurogenic inflammation associated with nasal polyps, at least in some cases [ 182 ]. At the level of the gastrointestinal tract, an increased dose of capsaicin causes a general irritation, ranging from a local warmth sensation to a painful burning sensation [ 435 ]. It is also known that capsaicin influences gastric activity [ 436 ]. Despite capsaicin having some gastroprotective effects, it also has the potential to induce ulcers [ 275 , 437 ]. Pathological effects in cases of capsaicin toxicity per body system. From a medical standpoint, in cases of capsaicin overexposure, common adverse effects are painful skin reactions and systemic effects, like nausea, vomiting, abdominal pain and diarrhoea accompanied by a burning sensation [ 438 ]; capsaicin is toxic in far lower doses in children compared to adults. In the case of eye exposure, following contact with pepper sprays, marked lacrimation, pain, conjunctivitis, and blepharospasm are common and may be aggravated by the presence of risk factors [ 439 , 440 ]. For local toxic reactions, a thorough decontamination of the skin and mucous membranes is recommended [ 441 ], involving water and antiacids [ 442 ]; furthermore, the treatment of systemic toxicity is based on the management of symptoms until capsaicin excretion [ 443 ]. Finally, a few fringe cases of capsaicin toxicity are reported in the medical literature, namely an acute polyneuropathy, presenting as Guillain-Barre syndrome following pepper spray exposure [ 444 ], the death of an infant after a capsaicin-containing traditional medicine was orally administered [ 445 ], and an acute MI in a patient with a transdermal capsaicin patch [ 446 ].

The most prominent pungent principle in the hot peppers ( Capsicum annuum ) of the genus Capsicum [ 1 ] is capsaicin (8-methyl- N -vanillyl-6-nonenamide), an organic nitrogenous compound within the lipid group [ 2 ]. It must be noted that the name capsaicin was originally used to refer to a multitude of substances originally isolated from C. oleoresin ; these compounds are now known as capsaicinoids [ 3 ], a distinction made after the 1960s [ 4 ]. Interestingly, it has been discovered that the cultivation of chilli peppers began around the 5th millennium BC [ 5 ], thus rendering them amongst the oldest cultivated plants; their origin is estimated to be somewhere in Bolivia [ 6 ]. Chilli peppers came to Europe only after the discovery of the New World and the subsequent Columbian Exchange, which had far-reaching consequences [ 7 ]; this is hardly surprising as numerous foodstuffs followed this historical process [ 8 , 9 , 10 ]. Subsequently, chilli peppers were swiftly adopted by many cultures and, as such, are ingredients in many local and traditional dishes [ 11 ]. It is believed that the synthesis of capsaicin within the plant is part of a defence mechanism developed against consumption by herbivores and micro-organism infestations [ 12 ]; however, not all chillies are pungent [ 13 ]. Extracted initially as an impure formulation by C.F. Bucholz (1770–1818), it was termed “capsicin” [ 14 , 15 ]. The original compound, isolated almost completely in 1876 by J.C. Thresh (1850–1932) [ 16 , 17 , 18 ], was a colourless substance of a crystalline structure—though purified in the 1870s, the first description of its structure is recorded in 1919 [ 19 ]—this is not surprising given that the complete isolation of the compound was achieved only in 1898 by K. Micko [ 20 , 21 ]. Based on the original isolation of capsaicin and the identification of its chemical and physical properties, capsaicinoids, of which capsaicin is a member, are defined as chemical compounds which have similar structures and properties as capsaicin [ 22 ]. Regarding capsaicin in particular, in its pure form, it is a solid, colourless, hydrophobic, highly volatile and highly pungent substance [ 23 ]; if heated to decomposition (80–140 °C), the fumes emitted are toxic nitrogen oxides [ 24 ]. Its chemical formula is C 18 H 27 NO 3 [ 25 ]. Capsaicin naturally occurs in its trans form, although a cis-isomer also exists [ 26 ]. The biosynthetic path of capsaicin, as described in research [ 27 ], involves a chemical reaction between vanillylamine and 7-methyloct-5-ene-1-carboxylic acid chloride; this reaction takes place in the fleshy parts of the fruits. In the seeds of these fruits, no capsaicin is produced; however, the white part of their inner wall contains the highest capsaicin concentration, and it is where the seeds are attached [ 26 ]. It is interesting to note that under stress conditions, the capsaicin production of the plant increases [ 28 , 29 ]. Currently, artificial synthesis of capsaicin is possible using a number of different methods [ 30 ]. The first artificial synthesis of capsaicin was recorded in 1930 [ 31 ]; a number of methods have been developed lately to enhance its production [ 32 , 33 , 34 , 35 ], given its high demand for research and applications. The most oft-used scale to measure capsaicin’s, or indeed any other compound’s, pungency is the Scoville Heat Unit (SHU) scale, proposed in the early 1990s [ 36 ]; this is based on the subjective pungency perception of people consuming pungent substances and foods. It is a linear scale, and it can exceed even 10 6 SHU for the hottest peppers containing the highest amounts of capsaicinoids [ 37 ]. Due to its properties, capsaicin has a number of already established clinical and industrial uses ( Table 1 ), while a number of novel clinical applications are under discussion. Outside of medical applications, the very potent irritative effect of capsaicin on mucosae [ 38 ] means that it constitutes an important component in pepper spray products [ 39 , 40 , 41 , 42 ]. In this review, we will present a comprehensive analysis of the pharmacodynamics and pharmacokinetics of capsaicin and elaborate on its pharmacotoxicity. Given that our study focuses on the pharmacological properties of capsaicin, the most prominent local, systemic and anticarcinogenic applications of capsaicin will be presented in detail. The applications of capsaicin in traditional medicine will also be addressed, and current evidence of the most promising avenues of future research will be reported.

Currently, as a phytomedical compound, capsaicin has been demonstrated to have analgesic, antioxidant, anti-inflammatory, anti-cancer, cardio-protective, and metabolic modulation effects. Capsaicin analogues are also currently evaluated for such properties [ 447 ]. A recent study even documented capsaicin-induced inhibition of cell senescence [ 448 ], while another proposed that capsaicin may even be a viable management option in cases of schizophrenia [ 449 ]; regarding the cardio-protective effects of capsaicin, it might even be possible to use it to alleviate acute myocardial injury [ 450 ]. Considering that the majority of such mechanisms are caused by the activation and subsequent inactivation of the TRPV1 receptor, further studies of the role of this receptor may yield useful results regarding both diagnostic and treatment methods. Notably, TRPV1 belongs to a category of receptors recently characterised as extra-oral taste receptors, i.e., oral receptors not found in the oral cavity [ 451 , 452 ]. Outside of the oral cavity, these receptors appear to have immune system-related and bronchorelaxation-associated properties [ 453 , 454 ]; it is known that taste receptors and their associated effector biomolecules are expressed in tuft-1 cells [ 455 , 456 , 457 , 458 ]. The characteristic morphology of these cells has been described in detail by Hendel et al. [ 459 ]; their localisation is quite diverse [ 455 , 460 , 461 ]. Moreover, it seems that they are also involved in the regulation of the immune system [ 462 ]. A significant challenge of using capsaicin for its potent therapeutic properties is its poor bioavailability due to its quick metabolisation [ 463 ]. It is believed that in vivo capsaicin concentrations achieved through conventional routes of administration are inferior to the levels that demonstrated effectiveness in vitro [ 464 ]. This is due to variations and limitations in absorption, distribution, and excretion, which limit the permeation of capsaicin to the desired action site. Therefore, in vivo, replication of the effects observed in vitro is an increasing focus of interest, and effective methods are being researched in this regard [ 465 , 466 , 467 ]. Furthermore, systemic capsaicin administration is associated with a number of side effects, and so in order to produce the maximum possible therapeutic effect in the target tissue while, at the same time, minimising side effects, it is desirable to control its delivery with precision. This can be performed, as previously alluded to, by employing novel delivery systems, namely liposomes, micelles, micro-emulsions and nano-emulsions [ 468 , 469 ], colloidal capsules and solid nanoparticles [ 470 ]; another avenue concerning implant-associated infections [ 471 ] would be the integration of capsaicin into 3D printed biomaterials [ 472 ]. These improve oral bioavailability for targeted applications, including anti-cancer endeavours [ 473 , 474 ]. Combination of capsaicin with bioenhancing substances such as piperine can prevent its degradation and increase its systemic concentration [ 475 , 476 ]. A number of nanostructured lipid carriers can also be incorporated into transdermal patches to reduce local side effects, such as skin irritation and erythema [ 477 ]—the use of capsaicin in the management and treatment of skin pathologies is a promising and rapidly developing field [ 118 ]. A future perspective on increasing capsaicin concentration for anti-cancer effects is also its integration into a delivery system that responds to physiologic triggers such as temperature or local pH, therefore optimising its clinical use and expanding its potential as an anti-cancer therapeutic agent [ 156 , 478 , 479 ]. Capsaicin, as well as other phytochemicals with promising medicinal properties [ 480 ], may benefit from such novel delivery methods. A novel way for capsaicin delivery for a particular case of colorectal cancer has recently been explored by Rajput et al. [ 481 ]. In cases of inflammation, either local or systemic, capsaicin may offer a good alternative if the common anti-inflammatory drugs are not tolerated due to their side effects. The combination of capsaicin with acupuncture may also be useful in that regard, given that acupuncture is already quite effective in the treatment of pain (e.g., [ 482 , 483 , 484 , 485 ]) and other inflammatory states (e.g., [ 486 , 487 , 488 ]), and the relevant research interest is increasing [ 489 ]. Of particular interest is the emerging research on the antibacterial (e.g., [ 490 , 491 , 492 ]), antifungal (e.g., [ 493 , 494 ]), antiviral (e.g., [ 495 ]) and antiparasitic (e.g., [ 496 ]) properties of capsaicin. Already, a number of different phytomedical compounds and their derivatives are being researched for their antimicrobial/antiviral potential, such as kaempferol [ 497 , 498 , 499 , 500 ], quercetin [ 501 , 502 , 503 ], curcumin [ 504 , 505 , 506 , 507 ], coumarin [ 508 , 509 , 510 ], and allicin [ 511 , 512 , 513 ]. This is especially important when considering the increasing antimicrobial resistance (e.g., [ 514 , 515 , 516 , 517 , 518 , 519 , 520 ]) and the occasional severe side-effects like allergies to antimicrobial drugs (e.g., antibiotics [ 521 , 522 ]) and especially some antiparasitic drugs ([ 523 ] and references therein). Furthermore, other research directions could involve capsaicin’s role in modulating intestinal microbiota, of whose diversity it increases; this opens new possibilities in combating the complications of various GIT-related illnesses [ 524 , 525 ] through the modulation of the gut-brain axis and immune system interaction [ 526 ]. Potential applications of capsaicin in pulmonary and gastrointestinal cancers have also been concisely summarised in recent papers [ 527 , 528 ]. An interesting research direction could also involve the application of capsaicin at acupuncture points, aside from the aforementioned combination of capsaicin and acupuncture; indeed, based on the positive results of three clinical trials [ 63 , 64 , 65 ] where capsaicin was applied locally at acupuncture points, larger-scale research for a number of conditions can be undertaken, following the same principle—similar positive research results were also reported by Kim et al. [ 194 , 197 ]. When considering the proposed special properties of meridians in interstitial fluid—or generally fluid—circulation [ 529 , 530 , 531 , 532 ], it is compelling to consider the potential for applying specialised cutaneous treatment schemes, using capsaicin or even other bioactive compounds, in this manner.

Capsaicin is a potent phytochemical substance that has numerous health benefits. It can be used medicinally both in systemic and local administration. At the same time, the potential toxicity of capsaicin poses an important constraint on its medicinal use, especially in certain sensitive tissues such as the eyes. Already, capsaicin forms part of a number of medical traditions, and such proposed medicinal uses warrant further research. The association between capsaicin and acupuncture must also be explored more thoroughly. Based on the data presented in this paper, we conclude that capsaicin may be used as a monotherapy or adjunct therapy in the treatment or management of a number of pathologies.