Pruritogens: Substances That Cause Itching

Pruritogens (from Latin prurigo — itching) are substances that induce pruritus (itching sensation). These compounds are insufficiently addressed in the literature on non-lethal chemical agents, despite their significant historical application by British intelligence services for sabotage operations in German-occupied territories during World War II.

The scientific and military interest in non-lethal chemical agents capable of causing incapacitation, pain, or distress increased substantially following the successful deployment of mustard gas during World War I. From this perspective, pruritogens presented potential advantages over mustard agents, as they operated through more controlled mechanisms without causing severe dermatological manifestations such as blisters and ulcers. Furthermore, these compounds demonstrated the capability to circumvent standard gas mask protection systems, which were otherwise effective against all known irritant agents of that period.

During 1917–1919, the British War Office conducted field trials of novel chemical warfare agents, including an unconventional agent in the form of glass particulate matter. While detailed reports of its physiological effects on human subjects were not publicly documented, it was established that glass fibers and particulates induced severe pruritic responses upon dermal contact. Subsequently, British researchers concluded that the deployment of glass particles in aerosol form demonstrated insufficient tactical efficacy under combat conditions.[33]

In his post-World War I monograph, prominent Polish toxicologist W. Lindeman identified ethylene thiocyanate as one of the most potent pruritogenic chemical agents, suggesting its potential application as a chemical warfare agent.[35] Additional possible candidate with documented pruritogenic properties include ethyl chlorocarbamate and o-chlorobenzalacetone.[36] However, the pruritogenic potency of these substances was determined to be insufficient for effective deployment as irritant agents.

Ethylene dithiocyanate	Ethyl chlorocarbamate	o-Chlorobenzalacetone	Isooctyl pyrogallol

During the 1920s and 1930s, the laboratory of prominent pharmacologist Ernest Fourneau, who concurrently served as a chemical weapons researcher for the French government, conducted investigations into the irritant properties of isooctyl pyrogallol. This compound, bearing structural similarity to the natural irritant laccol, demonstrated dose-dependent biological effects: at low concentrations, it induced pruritus in human subjects, while at higher doses, it exhibited vesicant properties characteristic of blister agents. The Fourneau laboratory synthesized approximately 100 kg of this chemical agent for subsequent artillery shell trials.[28]

Mucuna pruriens trichomes stuck in a finger
(foto: Armstrong W.P., 2010)

During World War II, British Special Operations Executive (SOE), also known as the Ministry of Ungentlemanly Warfare, made extensive use of itch-inducing agent for sabotage operations in occupied territories, aiming to undermine Wehrmacht soldiers' morale. Greek resistance fighters were the first to successfully test the "itching powder" — they liberally applied the secret British substance to the bed sheets of German soldiers quartered in homes and barracks. The German soldiers, suffering from constant unbearable itching, suspected nothing and believed they had fallen victim to lice infestation. Later, the itching powder was distributed to Denmark and Norway disguised as "foot powder." There, resistance members working in laundries began applying it to German officers' underwear, trousers, and shirt collars. In some cases, it was even introduced into contraceptives at brothels frequented by German servicemen.[26]

Norwegian resistance fighters achieved their greatest success when they gained access to German submarine crews' uniforms. In a quarterly report prepared by the British Special Operations Executive (SOE) for Winston Churchill, the secret service reported that the itching powder had successfully inflicted discomfort "in the more tender parts of the human anatomy" to 25,000 German sailors.[30]

There are two versions regarding the composition of the British itching powder. According to one version, it was made from microscopic glass fiber particles,[27] while another source suggests that "tiny seed hairs" were used, likely referring to cowhage (Mucuna pruriens) pods.[27]

During the 1968 Interagency Conference on the Tunnel Problem, U.S. military command evaluated various countermeasures against Viet Cong forces utilizing underground tunnel networks. Among the proposed biological deterrents, researchers investigated the potential application of microscopic barbed spines (nettles) derived from the cactus Opuntia rufida as a tunnel denial agent.[37]

The theoretical mechanism relied on the spines' ability to cause significant epidermal irritation and physical discomfort when contacted by personnel traversing treated tunnels, thereby rendering these passages temporarily unusable for enemy forces. However, this approach was ultimately abandoned in favor of alternative counter-tunnel methodologies that demonstrated greater operational potential.[37]

The last mention of itching powder as a potential incapacitating agent appears in a rather old U.S. Department of Defense document titled "Riot Control Analysis and Catalog" (1969). Among potential pruritogens, it lists cowhage (Mucuna pruriens), proteolytic enzymes, and acid solutions. The article also states that primary efforts should be directed toward finding a suitable synthetic substance.[11]

Over time, military chemists' interest in chemical pruritogens gradually waned, and in the subsequent half-century, no new information emerged about the development of chemical compounds capable of causing unbearable itching and suitable for use as incapacitating agents.

Itching Powders

Commercial "itching powders" typically contain ingredients that cause itching through mechanical skin irritation. Such powder consists of microscopic particles shaped like sharp needles or crystals with pointed edges, enabling them to penetrate the superficial layers of skin. Although manufacturers are reluctant to disclose their know-how, most commonly these "itching powders" are simply pulverized maple (Acer) seeds or the tiny hairs from cowhage (Mucuna pruriens). In Germany, "itching powder" is manufactured from rose cuticles (shown in the second image from the right at the top).[32]

Maple seeds	Cowhage pod	Rose hip	Opuntia glochids

Cowhage or Velvet bean (Mucuna pruriens). The alternative name of this climbing plant from the legume family speaks for itself — Stinging Cowitch. Trichomes (from Greek tríchōma — hair) — the orange hairs covering the fruit of this tropical plant are the most common component of "itching powders." The trichomes of Mucuna are so tiny that 450 trichomes weigh only 1 milligram.[10]

In Venezuela, during religious festivals, local pranksters blow Mucuna pruriens powder through paper tubes at passersby, condemning them to long hours of exhausting scratching. The trichomes have found a more noble application in traditional medicine — when mixed with honey, they serve as an anthelmintic (anti-worm) treatment.

Shelley and Arthur (1995), under contract with the U.S. Army, conducted a detailed experimental study of cowhage. They determined that just one trichome was sufficient to cause itching in 90% of subjects, with intense itching developing within 15–30 seconds and lasting on average 3–5 minutes[20]. The active compound in the trichomes is mucunain, a proteolytic enzyme that acts as an agonist of protease-activated receptors PAR₂ and PAR₄.[21]

Maple (Acer). When you rub together the V-shaped winged seeds (samaras) of maple trees, they shed microscopic hairs. By spending a little time on this activity, you can collect a full teaspoon of homemade "itching powder" from several dozen seeds.[6,7] This powder is sold in some American novelty shops specializing in "prank items." Similarly intense itching can be caused by the fuzzy seeds of sycamore trees.

Dog Rose (Rosa canina) — the finest hairs located on the inner surface of rose hips (especially wild varieties) cause intense itching when they contact skin. To obtain these cuticles, first collect the fruit's contents in a separate container, place them near boiling water for 10–15 minutes to absorb moisture, and then dry them.[7] There's a similar method for obtaining "itching powder" from regular rose cuticles, also known as the "Romeo and Juliet" method. The cuticle hairs located inside the rose bud are processed in the same way as the rose hip contents.[31]

Opuntia (Opuntia). As mentioned earlier, microscopic barbed spines (glochids) of cacti from the genus Opuntia cause an intense and prolonged itching sensation. Opuntia rufida, commonly known as the blind prickly pear, earned its name due to its glochids, which can cause eye injuries and potential blindness in grazing cattle. Glochids easily detach upon contact with skin or clothing, embedding themselves into the skin and causing severe irritation. In many cases, removing these "micro-splinters" requires the removal of the superficial layer of the epidermis, often necessitating thorough treatment of the affected area with a pumice stone.

Japanese Nettle (Urtica thunbergiana)

Japanese nettle (Urtica thunbergiana). The fact that severe skin itching can drive a person to madness was known even to the semi-mythical Japanese ninjas. They used nettle to produce a fine powder, which they sprinkled into an opponent’s underwear or down their collar as a form of sabotage. In 2006, Thai researchers uncovered the mechanism behind the irritant effects of this nettle, revealing that oxalic and tartaric acids — rather than histamine and serotonin, as previously assumed — were responsible for the painful reaction.[5] It is likely that microscopic crystals of these acids, when in contact with the skin, trigger the intense itching sensation.

Some bamboo species feature fuzzy hairs on their stems that can cause severe itching and dermatitis when they come into contact with human skin.[9] This little-known characteristic was significant enough to be mentioned in Combat Recon Tips of the Trade (B-720 TIPS), which specifically advised soldiers against hanging clothing on green bamboo shoots, as the fine hairs can act similarly to "itching powder."[12]

Glass wool is a potent and highly dangerous pruritogen. Dermatitis caused by glass wool is difficult to treat, and if its fibers get into the eyes, it can lead to blindness.

Pruritus Mechanisms and Experimental Pruritogens

The neurochemical mechanism underlying pruritus has not been fully identified to date. Specialized medical literature documents multiple endogenous substances involved in the pathogenesis of dermatological diseases accompanied by pruritic syndrome.[1] These biologically active compounds implement direct or indirect interaction with a set of specific receptors (more than ten), presumably associated with afferent transduction and perception of pruritic stimuli.

Peripheral itch mediators and their respective receptors in skin nerve terminal (Liu & Ji,2013)[38]

While it was previously believed that pain and itching have identical receptor mechanisms and are transmitted through the same C-fibers, data obtained in recent years increasingly points to the existence of specific itch receptors. According to Xinzhong Dong and his colleagues from Johns Hopkins University, MrgprA₃+ receptors that respond exclusively to substances causing itching are candidates for this role. MrgprA3+ neurons are located in the dorsal root ganglia and are responsible only for innervation of the epidermis, as the sensation of itching can only occur in the skin, unlike pain, which we can feel in muscles, joints, and various organs of the body.[18]

One of the most potent endogenous itch mediators is leukotriene B₄. Intradermal administration of 0.000 000 01 grams of leukotriene B₄ induced a half-hour episode of intense itching in rodents within 3 minutes.[2]

In humans, leukotriene B₄ elicits a cutaneous inflammatory response beginning at doses of 5 nanograms and reaching maximum intensity at 500 nanograms. The inflammatory reaction develops 12–24 hours post-exposure and persists for several days, ultimately leaving brownish pigmentation. It is hypothesized that leukotriene B₄ plays a crucial role in the pathogenesis of psoriasis, as psoriatic plaques contain elevated concentrations of this mediator.[3] Nociceptin (1–100 nmol), a peptide ligand for ORL-1 opioid receptors, demonstrates similar effects, though likely through distinct molecular mechanisms.[4]

Leukotriene B₄

Pruritus does not necessarily require direct chemical contact with the skin; it can also be triggered through alternative routes of drug administration. Thalassin, an alcoholic extract derived from sea anemone tentacles, induces intense pruritus in animals when administered intravenously at a dose of 0.1 mg/kg. Following thalassin injection in canine subjects, pronounced behavioral changes occur within 1–2 minutes: the animal becomes highly agitated, exhibits significant unsteadiness, and demonstrates sneezing behavior. The dog subsequently scratches its ears with its paws and rubs its nose against the floor. Within 10 minutes, the pruritus generalizes throughout the entire body, accompanied by erythema of the conjunctiva and abdominal skin.[29] In the early twentieth century, pharmacologists attempted to utilize thalassin for evaluating antipruritic pharmaceutical agents; however, they ultimately abandoned this approach in favor of safer methodologies due to thalassin's high toxicity and inconsistent composition.

Interleukin 31 (IL-31) is considered a more promising and safer pruritogen, which is involved in the pathogenesis of chronic inflammatory conditions such as atopic dermatitis and eczema. This substance induces intense and prolonged pruritus in mice, dogs, and non-human primates when administered intravenously at a dose of only 1 μg/kg.[34] It is possible that IL-31 may also demonstrate activity when delivered via inhalation.

Certain pharmaceutical agents are capable of inducing pruritus when administered orally. Chloroquine is considered the drug of choice for malaria prophylaxis; however, it causes intolerable itching in nearly 70% of individuals, forcing many to discontinue treatment

In addition to chemical and mechanical irritants, the sensation of itching in humans can be caused by stimulation with alternating electric current at a frequency of 50 Hz and a pulse duration of 2 ms and above.[23]

Most known synthetic and natural pruritogens exhibit activity in a narrow dose range and only when administered subepidermally, making it impossible to use them as incapacitants. Using penetrants like DMSO as carriers is ineffective due to the peptide nature of most highly active pruritogens.​​​​​​​​​​​​​​​​

In experimental medicine, processed trichomes of Cowhage (Mucuna pruriens) are sometimes used for intradermal injections of pruritogens. For this purpose, they are first heated to a specific temperature in an autoclave, then impregnated with a pruritogen solution and dried. This technique was proposed and successfully tested by Sikand P. et al. with capsaicin, histamine, and BAM8-22. With a trichome length of 2 cm, diameter of 1–3 μm, and using solutions with 10% concentration of the active substance for impregnation, each such "micro-syringe" is capable of delivering approximately 0.000 003 milligrams of the active substance into the body. However, even this amount of histamine proved sufficient to cause an itching attack, even more intense than from an untreated trichome.[19,22] For comparison, the substance BAM8-22 causes itching when only 120 picograms, or 0.000 000 12  milligrams, are administered.[19]

Trichomes of velvet bean (left), rose hip cuticle hairs (center), and glass wool (right) at high magnification

With this method of administration, high efficiency is achieved with minimal risk of side effects, as submicrogramic quantities of the active substance enter the body. It is obvious that other substances with high biological activity such as algogens, toxins (XR, PG), and bioregulators that cannot independently penetrate intact skin can be introduced intradermally in a similar manner.

Treatment of Lesions

To treat itching caused by mechanical irritants ("itching powders", trichomes, glochidia, fiberglass or glass wool), it is recommended to:

• remove contaminated clothing;
• under no circumstances touch or scratch the affected areas of the body;
• if possible, use a magnifying glass and tweezers to remove visible needles or hairs;
• rinse the skin with a strong stream of cool (!) water in the shower without using a washcloth or soap; do not rub the skin with a towel;
• mechanically remove the irritant using adhesive tape (medical tape, Scotch tape, or in extreme cases — duct tape), depilatory wax, or even modeling clay.

If itching persists, treatment with cooling, antihistamine, and anesthetic ointments and creams may be necessary. In severe cases, local corticosteroid therapy is indicated.

It is unknown whether a chemical pruritogen suitable for use as an incapacitant has been found, so treatment is not considered.