Unravelling the potential of insects for medicinal purposes – A comprehensive review

Entomotherapy, the use of insects for medicinal purposes, has been practised for centuries in many countries around the world. More than 2100 edible insect species are eaten by humans, but little is known about the possibility of using these insects as a promising alternative to traditional pharmaceuticals for treating diseases. This review offers a fundamental understanding of the therapeutic applications of insects and how they might be used in medicine. In this review, 235 insect species from 15 orders are reported to be used as medicine. Hymenoptera contains the largest medicinal insect species, followed by Coleoptera, Orthoptera, Lepidoptera, and Blattodea. Scientists have examined and validated the potential uses of insects along with their products and by-products in treating various diseases, and records show that they are primarily used to treat digestive and skin disorders. Insects are known to be rich sources of bioactive compounds, explaining their therapeutic features such as anti-inflammatory, antimicrobial, antiviral, and so on. Challenges associated with the consumption of insects (entomophagy) and their therapeutic uses include regulation barriers and consumer acceptance. Moreover, the overexploitation of medicinal insects in their natural habitat has led to a population crisis, thus necessitating the investigation and development of their mass-rearing procedure. Lastly, this review suggests potential directions for developing insects used in medicine and offers advice for scientists interested in entomotherapy. In future, entomotherapy may become a sustainable and cost-effective solution for treating various ailments and has the potential to revolutionize modern medicine.

Entomotherapy, the use of insects for medicinal purposes, has been practised for centuries in many countries around the world. More than 2100 edible insect species are eaten by humans, but little is known about the possibility of using these insects as a promising alternative to traditional pharmaceuticals for treating diseases. This review offers a fundamental understanding of the therapeutic applications of insects and how they might be used in medicine. In this review, 235 insect species from 15 orders are reported to be used as medicine. Hymenoptera contains the largest medicinal insect species, followed by Coleoptera, Orthoptera, Lepidoptera, and Blattodea. Scientists have examined and validated the potential uses of insects along with their products and by-products in treating various diseases, and records show that they are primarily used to treat digestive and skin disorders. Insects are known to be rich sources of bioactive compounds, explaining their therapeutic features such as anti-inflammatory, antimicrobial, antiviral, and so on. Challenges associated with the consumption of insects (entomophagy) and their therapeutic uses include regulation barriers and consumer acceptance. Moreover, the overexploitation of medicinal insects in their natural habitat has led to a population crisis, thus necessitating the investigation and development of their mass-rearing procedure. Lastly, this review suggests potential directions for developing insects used in medicine and offers advice for scientists interested in entomotherapy. In future, entomotherapy may become a sustainable and cost-effective solution for treating various ailments and has the potential to revolutionize modern medicine.

Introduction
Entomotherapy is another name for using insects and insect-derived products for therapeutic purposes [1,2]. Insects and their derived products contain natural compounds with a wide range of biological significance, including antibacterial, antifungal, antiviral, anticancer, antioxidant, anti-inflammatory, and immunomodulatory properties [3][4][5][6]. Insects are used as live, cooked, ground, infusions, plasters, salves, ointments, and various other ways [6]. Due to these properties, many communities worldwide have used insects for treating illness. For instance, communities in countries like India, China, and Thailand use insects on the advice of local doctors and elders to treat ailments, such as kidney disease, swelling, intestinal disorders, fortified blood, postpartum hemorrhage, lung diseases like asthma and chronic cough, liver and stomach ailments, toothaches, rheumatism, and other conditions. Moreover, some tribes use bedbugs to treat pain and inflammation in the leg fingers caused by nail insertion or other injuries, while mud from the nest of termites is used to treat inflammation in the body. Several studies have also shown that honey, honeybee larvae and pupae are utilized for various health conditions, including gastrointestinal disorders, gastric problems, mental distress, treatment of external wounds, and maggot therapy [7][8][9][10].
Entomotherapy has been practised in many countries around the world. According to Wigglesworth [11], many people in Europe throughout the seventeenth century believed that insects had some therapeutic value. These Europeans used insects to treat many health-related complications, such as epilepsy, earaches, scratches, rheumatism and anaemia [12]. Recent research into the antitumoral potential of the Chartergellus-CP1 peptide found in Chartergellus communis wasp venom in two different breast cancer cell lines (HR+ and triple-negative) showed encouraging results by killing just cancer cells while leaving healthy cells alone [13]. Blister beetles were used as an aphrodisiac throughout Europe, but recent advances show that they can also reduce pain from kidney stones, urinary tract infections and burns [14]. According to Verma and Prasad [15], these beetles contain cantharidin, which has a protein blocker that fights infections. These proteins can target only the infected cells, making them ideal for use in the immune system's fight against infections. Despite these therapeutic uses of insects and insect-based products, many studies have mainly focussed on their nutritional properties. In contrast to earlier studies, the information in our review offers a more fundamental understanding of the medicinal applications of insects and how they might be used in contemporary medicine. A thorough review of the literature is given, and the history, effects, and opportunities associated with the use of various insect species worldwide are discussed, focusing on papers highlighting the identification of insects to the lowest taxonomic rank possible and their publications in peer-reviewed journals.
In this review, we also discussed many insect species used for medicinal purposes, at which stages these species are utilized, and the impact of these insects on human health. We examine if entomotherapy is met with the same opposition as entomophagy. The earlier ideas of gathering insects, the requirement for industrial manufacturing to create significant amounts of insect-based medication, and what insect mass production would entail are discussed. Our review suggests potential directions for developing insects used in medicine and offers advice for scientists interested in entomotherapy.

History and evolution of the use of insects for medicinal purposes
Insects in medicine have a long history of application in many societies worldwide by different tribes. Medicinal uses of insects, such as silkworms (Bombyx mori L.), date back to at least 3000 years in China. At the same time, honeybees (Apis mellifera L.) were first recorded during the Xizho Dynasty (about 1100-771 B.C.). Tao Hongjing's "Mingyi Bielu" (Southern and Northern Dynasties, 420-589 A.D.) expanded "Shennong Bencaojing" to include information on nine additional species of medicinal insects. In his book "Compendium of Materia Medica" (1587), Li Shizhen listed seventy-three different insects used for medical purposes. As a result, 105 bug species were included in the supplementary volume to the "Compendium of Materia Medica" by Zhao Xuemin (Qing Dynasty, 1616-1911 A.D.). According to Robert James, who quoted the Dioscorides, "grasshoppers in a suffumigation relieve under a dysury (difficult micturition), especially as is incident to the female sex". When insects are bruised and mixed with sugar, they are used to treat ulcers and also serve as dewormers [16]. In some parts of the world, earwigs were used to treat convulsion by first drying, powdering and mixing it with the urine of hare to treat ear complications [16]. Research has shown that the Maya employed maggots for therapeutic purposes 1000 years ago [17]. The lac bug (Kerria lacca Kerr.) has been used as medicines since the 3rd century [18].
In some parts of Brazil, ants mixed with sugar and added to coffee or juice was useful in treating diseases associated with vision [19]. The therapeutic uses of insects have been evolving since ancient times [20]. For instance, silkworm pupae were only used for one purpose, that was as feed for livestock [21]. However, they have been recently used in modern medicine [22]. Recent advances in entomotherapy include maggot therapy, which involves the selective removal of necrotic tissue from soft tissue wounds with the insertion of life, disinfected blowfly larvae [23]. There have been recent advancements in the use of bees in apitherapy. Melittin, a key peptide found in bee venom, has shown promise in treating inflammation associated with rheumatoid arthritis and multiple sclerosis. Melittin blocks the expression of genes for inflammation, thereby reducing pain. Apitherapy has also provided more insight into its application to treat diseases, like Parkinson's disease by analysing the effects of propolis and royal jelly on the disease [24].
At present, there are about 1000 insects that have been documented to have medicinal properties in different countries worldwide, and includes Africa, India, Japan, Korea, South America, Spain, Tibet and Turkey [25,26]. However, out of the 1000 insects in medicine, about half of them from 70 genera, 63 families and 14 orders have been reported from China. In the Tibetan region of China, eleven insects, including flies, ants, butterflies, cicadas, and four kinds of beetles, such as diving beetles and blister beetles, were identified as insects with medicinal properties [27]. Apart from China, at least 50 different human diseases and conditions had been linked to the use of 50 different insect species from 28 families and 11 orders, have been recorded from India [28].
A large number of insect species belonging to different orders, such as Blattodea, Coleoptera, Diptera, Odonata, Hemiptera, Hymenoptera, Lepidoptera, Mantodea, Orthoptera, that have been useful in the treatment of various diseases are presented in Table 1 and

Insect species used for medicinal purposes and their associated stage being used
In total, 235 valid species were documented in several literatures that summarized insects used in folk medicine, which include insects from China [65,66], India [28], Africa [39], and Latin America [63]. Table 2 listed all the 235 species from 15 different orders, within which Hymenoptera contains the largest medicinal insect species count (62 species), followed by Coleoptera (47), Orthoptera (28), Lepidoptera (23), and Blattodea (21). The other orders contain much less (e.g., ≤11) species, which sum up to 55. At the family level, Apidae (27) contains the largest medicinal insect species documented, followed by Vespidae (19), Formicidae (15), Gryllidae  (11), Cerambycidae (10), Meloidae (9), Termitidae (9), Acrididae (8), Libellulidae (8), Cicadidae (8), and Mantidae (7), which sum up to 50% of the 235 species documented. Some genera contain more than one medicinal insect species. For example, seven species were reported in genus Melipona, seven species were reported in genus Vespa, and another seven species were reported in genus Apis. Among those 235 species, 151 were documented with the specific stage or product (e.g., feces, nest, etc.) used. Adult stage (90 species) was the most documented stage, followed by larvae/nymphs (60), pupae/cocoon (13), and eggs (7). The usage of adults and larvae/nymph are distributed widely among different orders (e.g., 2/3 orders were documented). On the contrary, the usage of eggs (e. g., Lepidoptera and Mantodea) and pupae/cocoon (e.g., Hymenoptera and Lepidoptera) are limited in two orders, respectively. Besides, fungus infected larvae are only documented in three species in Lepidoptera, which are the Beauveria bassiana infected Bombyx     Other than insects per se, byproducts from 31 species were documented. Byproducts from species in Hymenoptera are the most documented (e.g., 18 out of 31 species), for example, bee wax, honey, royal jelly, bee pollen, bee comb, and bee venom from the family Apidae, bee comb from the family Vespidae, and nest from the family Formicidae (Table 2).

Health effects of medicinal insects and their associated mechanisms
The international classification of diseases system ICD10 (Table 3) is used here to sort the health effects of insects mentioned in literature except wound healing, which cannot be sorted in a single group of disease. The ICD10 system was published by the World Health Organization (WHO) in 1994 (more details can be found in the ICD10 Interactive Self Learning Tool, https://apps.who.int/ classifications/apps/icd/icd10training/). Modern research (i.e., 2012-2022) that studied medicinal functions with species family documented in the above five summarized literatures [28,39,63,65,66] were screened out on Web of Science™. We identified ~300 articles, which cover 23 families. The focus on health effects of insects in modern medicine has changed significantly compared to folk medicine. Insects that used to fight against infectious and parasitic diseases (ICD A00-B99) counted ~36% of the total research, followed by insects promote wound healing (counted ~17%) and anti-neoplasms (ICD C00-D49, counted ~15%). Heatmap analysis (Fig. 3a-c) showed the association between diseases and the insect families. Insect families used in different groups of diseases are diverse except wound healing, which was heavily focused on the use of Calliphoridae (Fig. 3b). For example, infection related diseases were frequently used with insects in Calliphoridae, Muscidae, Apidae, and Formicidae. Neoplasm studies frequently used insects in Corydiidae, Meloidae, and Bombycidae. Distributions of associated disease in each insect family vary (Fig. 3c). For example, Blattidae was mostly used in digestive system disease research. Cicadidae and Scollidae were mostly used in nervous system disease research.
The choice of insects in disease research seems to be heavily impacted by the documentary of folk medicine and the market availability. Below is a detailed description of functions mentioned in modern research based on the ICD system with mechanisms (Table 4) and ingredients (Table 5) documented.

ICD10 code
Disease classified A00-B99 Certain infectious and parasitic diseases C00-D49 Neoplasms D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism E00-E89 Endocrine, nutritional, and metabolic diseases F01-F99 Mental, Behavioral and Neurodevelopmental disorders G00-G99 Diseases of the nervous system H00-H59 Diseases of the eye and adnexa H60-H95 Diseases of the ear and mastoid process I00-I99 Diseases of the circulatory system J00-J99 Diseases of the respiratory system K00-K95 Diseases of the digestive system L00-L99 Diseases of the skin and subcutaneous tissue M00-M99 Diseases of the musculoskeletal system and connective tissue N00-N99 Diseases of the genitourinary system O00-O99 Pregnancy, childbirth, and the puerperium P00-P96 Certain conditions originating in the perinatal period Q00-Q99 Congenital malformations, deformations, and chromosomal abnormalities R00-R99 Symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified S00-T88 Injury, poisoning and certain other consequences of external causes U00-U85 Codes for special purposes V00-Y99 External causes of morbidity Z00-Z99 Factors influencing health status and contact with health services

S.A. Siddiqui et al.
cordycepin [161], and cecropin [146] from silkworms (Bombycidae) have gain many attentions with their anti-tumor effects. Since the cantharidin has certain toxic side effects, a synthetic derivation of cantharidin named noncantharidin has been developed and widely used in modern anti-tumor medicine [81]. Eupolyphaga sinensis (Walker) (Blattodea: Corydiidae) is another well-known traditional Chinese anti-tumor medicine, from which the extracted polysaccharide [74] and a protein named EPS72 [125] have been determined as the active ingredients. Recently, chitosan derivations from scarab beetles (Scarabaeidae) [155] and blowflies (Calliphoridae) [156] were determined to be the effective ingredients as well.

Health effects associated with blood and blood-forming organs and certain disorders involving the immune mechanism (D50-D89)
Not much research can be classified in this group besides nutritional anemia. Insects are rich in nutrients and have been proved to be effective diet supplements [226]. For example, the consumption of cricket could help to prevent children nutritional anemia by providing sufficient energy, iron, and zinc [227].

Anti-hyperglycemia and anti-hyperlipidemia are the two major effects associated with endocrine, nutritional, and metabolic diseases (E00-E89)
The anti-hyperglycemic effect works through advanced glycation end products (AGEs) inhibition [78], α-glucosidase inhibition [176], and beta cell improvement [79]. Active ingredients, for example flavonoids and free amino acids from B. mori [80] and epicatechin and p-coumaric from A. mellifera propolis [165] have shown the ability to regulate blood sugar and prevent/treat diabetes. Anti-hyperlipidemic effects works through energy metabolism balancing [82], AMPK/mTOR pathway activation [82], and cholesterol metabolism-related biochemical parameters regulation [83], and therefore showed obesity prevention potentials [167]. Peptides, for example, DP17 [82] and AR-9 isolated from E. sinensis [164] and Mastoparan B isolated from Vespa basalis Smith (Hymenoptera: Vespidae) [167] and glycosaminoglycan from Gryllus bimaculatus De Geer (Orthoptera: Gryllidae) [166] and Bombus ignitus (Smith) Fig. 3. Heatmap of associations between insect families and diseases. a) showed with numbers of papers; b) scaled by disease; and c) scaled by family of insect. International classification of diseases (ICD10) is used here to sort the diseases with code A to Z (https://www.icd10data.com/ ICD10CM/Codes). Wound healing is added since it does not belong to any ICD10 code. (Hymenoptera: Apidae) [166] have been determined to be the effective ingredients.

Anti-anxiety and anti-depression were the documented effects that associated with mental, behavioral, and neurodevelopmental disorders (F01-F99)
The bradykinin-related peptide isolated from Polybia paulista Ihering (Hymenoptera: Vespidae) venom was determined to be the active ingredients again anxiety, which may work with the B2-receptors and B1-receptors [85]. The silk syrup produced from B. mori cocoon was determined to have anti-depression effect, which may be due to its antioxidant and estrogenic properties [86].

Neuroprotection and venom immunotherapy are the major functions associated with nervous system (G00-G99)
The mechanisms of insect neuroprotective effects include antioxidation [87], anti-inflammation [87], cell cycle inhibition [87], and apoptosis prevention [88], which can prevent neurodegenerative diseases (e.g., Alzheimer's disease) [87], Parkinson's disease [170], Amyotrophic lateral sclerosis [228], and epilepsy [174]. Venom immunotherapy is an effective treatment for systemic allergic reactions to Hymenoptera venom. The potential mechanisms (e.g., the initial desensitization of effector cells, the regulation of IgG and IgE level, and the associated inflammatory effects) were recently reviewed by Demšar Luzar et al. [229]. Hymenoptera venom was widely documented as traditional medicine or therapy targeting the nervous system and has been studied and used in the modern medicinal system. Peptide [175] and melittin [88] isolated from venom are documented as the effective ingredients.

Hepatoprotection and gastroprotection are key effects associated with digestive system (K00-K95)
The inflammation reduction [101] and anti-oxidation [100] effects of insects play important role in against the digestive system disease such as diarrhea [181], gastric ulcer [102], and prevent liver damage after acute alcohol exposure [101]. Intestinal microbiota regulation is another key mechanism for gastroprotection [106,107]. Besides, neovascularization and growth factor expression enhancement were determined in preventing recurrence of gastric ulcer [102]. The gastroprotective effect of peptides isolated from B. mori [185], E. sinensis [109], Musca domestica L. (Diptera: Muscidae) [180], and P. americana [103] have been confirmed. Among the species tested, the P. americana gained a lot of attention in digestive system protection, from which the oligosaccharides [106] and an antimicrobial peptide (Periplanetasin-2) [103] have been identified as effective ingredients. The extract of P. americana has been developed into a commercial medicine named Kangfuxin solution in China [102].

Health effects associated with skin and subcutaneous tissue (L00-L99)
Besides the antibacterial function described in group A00-B99, the antioxidation and anti-inflammation effects of insects help to reduce psoriasis [177], dermatitis [2] and UVB-induced melanogenesis [110] and aging [112]. For example, silkworms B. mori have been used in skin protection for a long history. The cocoon sericin [187], freeze-dried silkworm powder [110], and even the feces [2] were determined contributed to skin protection.

Health effects associated with wound healing
Wound healing is one of the research hot spots in medicinal insects, which does not belong to any ICD 10 categories since many diseases can lead to wound formation. Wound healing can be separated into therapy with and without maggots. Debridement (i.e., the process of larval feeding on necrotic tissues), disinfection (i.e., anti-bacteria functions mentioned above) and wound healing (e.g., through keratinocytes stimulation [119], cell proliferation [122], blood coagulation [114], and pro-angiogenesis [122]) are the three main mechanisms. Lucilia sericata (Meigen) is the most used insect in maggot therapy. The excretions and secretions from maggot larvae have shown outstanding effects in wound healing, from which mainly proteins/enzymes (e.g., angiopoietin-1 enzyme [193] and serine protease [197] were determined effectively promote angiogenesis and cell proliferation. Besides, insect-derived products such as honey, bee venom, chitosan, and sericin have used in wound healing [233].

Medicinal uses of common edible insects
Most forms of traditional medicine rely on plants and plant-derived components [26]. Nevertheless, for centuries, animals are often used as part of folk pharmacopoeia [28,234,235]. Both domesticated and wild fauna resources are used in zootherapy, which involves the application of animals to treat diseases and include them in magic rituals and religious rites [236]. Medicines originating from animals are made either directly from the whole animal or its parts [235]. Insects in medicine fall under an umbrella terminology called "integrative medicine", which refers to a medical practice that blends traditional treatment with complementary and alternative medicine techniques and, has been safe and effective through scientific research [237][238][239][240]. Edible insects are rich in proteins, fats, fiber, vitamins, and minerals but also seem to contain large amounts of polyphenols able to have a key role in specific bioactivities as antioxidant functions. They also exert other activities, such as anti-inflammatory and anticancer activity, antityrosinase, antigenotoxic, and pancreatic lipase inhibitory activities.   Because of bee's medicinal and nutritional benefits, honey has been utilized for thousands of years [241]. In many societies, honey, a bee product, has long been regarded as a therapeutic remedy, and there are about 300 types of honey worldwide [242]. Honey, bee pollen, propolis, royal jelly, beeswax, and even bee venom are some honeybee products that have been used in folk medicine for millennia across the globe [243]. Anti-inflammatory, antimicrobial, antifungal, antiviral, and antioxidant properties have all been observed in these insect-derived products. These antioxidant, antimicrobial, and other medicinal properties are more effective than sucrose in treating diabetes [242]. Another important product from bees, bee venom, has been utilized as a treatment method in East Asia since the second century, making it one of the region's oldest medical practicesf [244]. The chemical structure of bee venom is intricate, involving many different enzymes, peptides, proteins, smaller molecules (amino acids, catecholamines, carbohydrates, and minerals), and lipids that make up honeybee venom [245]. It also contains Melittin, apamin, MCD peptide, histamine, hyaluronidase, and phospholipase-A2 for bee venom's primary components. However, melitin, a peptide obtained from the European honeybee Apis mellifera has been well-studied by several authors [246]. Due to its high cytolytic action, it has proven to be highly effective against tumours [247,248]. Bee venom is an allergen agent that causes Asthma, allergic rhinoconjunctivitis, and atopic eczema by stimulating the production of allergen specific CD4 + T cells in susceptible individuals [245]. Bees provide health benefits because they contain many different metabolites, such as folic acid, thiamine, biotin, niacin, tocopherol, polyphenols, phytosterols, and enzymes and coenzymes. The beneficial properties include antioxidant, antibacterial, antifungal, and hepatoprotective [241,249]. A recent study by Amr et al. [250] on female rats showed that boneybee products had the potential to reduce oxidative stress, increase cadmium (Cd) excretion via the kidneys, and modify intestinal absorption of the metal.
The larvae of the Australian Sawfly contain novel macrocarpa and grandinol. These chemical components were assessed against Bacillus subtilis and showed positive antimicrobial effects against the bacteria [6,251]. The larvae of Sawfly Tenthredo zonula Klug also contain phenolic compounds, such as flavonoid glycosides, flavonol oligoglycosides, and naphthodianthrones, and have been evaluated for their health properties [252].
The Chinese black ant (Polyrhachis dives) is an edible insect with kidney-detoxifying and antiinflammatory properties [253]. The ants contain several compounds essential for immunosuppressive, antinflammatory and renoprotective effects. Recently, several compounds were isolated from the species (Fig. 4).
The Chinese medicinal Insect Blaps japanensis, has been used to treat many diseases, including fever, cough, rheumatism, cancer, and inflammatory disorders. The species contains blapsols (Fig. 5a) and dopamine dimers ( Fig. 5b and 5c). These chemical components have been evaluated for their effectiveness against cyclooxygenase (COX) enzymes COX-1 and COX-2. The enzymes catalyze the conversion of arachidonic acid to prostaglandins, which is useful in pain, fever, and inflammation [6,254,255].
The silkworm pupae are helpful to human health because of their high nutritional value and the many pharmacological effects they can have when consumed [73]. A vasorelaxant derived from the pupae of Bombyx mori, dimethyl adenosine, inhibits phosphodiesterase and stimulates nitric oxide production in endothelial cells, thus serving as a potential drug for treating vasculogenic impotence [22].   Chinese, Korean, and Japanese acupuncture and traditional medicine practitioners have used bee venom (B⋅V.) to treat inflammatory illnesses by administering a sterile bee sting or injecting a prepared B.V. solution [256,257]. The use of insects and insect-derived products for disease treatment is substantially lower than typically claimed in Asia, Europe and Africa [258]. A study conducted in Kadiogo and Houet showed that about 19 insects belonging to 6 orders were important in treating about 78 different diseases and conditions, such as vomiting, headaches, deafness, pain and Inflammation [39]. Many insects are also used to treat different kinds of diseases in India [28]. The insects and insect-derived products used as medicine in India and Burkina Faso are illustrated in Fig. 6, in which the Giant water bug Lethocerus indicus, dragonfly nymphs, large timber-boring larvae, freshly harvested Apis florea bee comb, nest entrances of stingless bees, Vespa mandarinia comb, blister beetle Mylabris sp., larvae of antlion and Myrmeleon sp., are recorded from Nagaland (Fig. 6 a-i) and larvae of Cossus sp., larvae of banana skipper Erionota torus, Epilambra sp. Cockroach, Periplaneta Americana, Macrotermes sp., Apis mellifera, Pachycondyla sp., Lytta sp., and Camponotus maculatus are reported from Kadiogo and Houët provinces (Fig. 6 j-r) [28,39]. Although the Angami people of India employ the larvae of the banana skipper Erionata torus to treat dangerous animal bites, the Lotha people utilise them as an aphrodisiac. Mylabris sp. Is used to treat blisters and warts in India and are also included in the traditional Chinese medical pharmacopoeia and Korean medical pharmacopoeia. A study by Ouango et al. [39] showed that insects had been used in Burkina Faso to treat many diseases. The traditional healers in Burkina Faso utilise the cockroach Periplaneta americana (Fig. 6), to relieve ear pain. Microtermi spp. Is also used to treat diarrhea and fractures in Burkina Faso. Asthma, rheumatological pathologies, bladder lithiasis, burns, constipation, difficulty breathing, general fatigue, gynaecological problems, heart diseases, hip pain, insomnia, intestinal helminthiasis, and voice extinction are just some of the many conditions that can be helped by medicines derived from Apis mellifera. The bees are also used to reat female infertility and male impotence. The blister beetle Lytta vesicatoria is urinary track infection. Insects and insect-based substances have a long history of usage as food and feed in many parts of the world [259]. In many regions of the world, entomotherapy is used by various segments of society. In Northeast India, locals have identified twelve insect species as having medicinal value. These insects are being employed by the tribes and used to cure a wide range of illnesses in humans and domestic animals [260]. Coughs, fevers, nighttime emetic production, burns, and gastrointestinal illness were all treated with one of nine species found in Bangladesh [1,28].

Regulations of entomotherapy and entomophagy
Eating insects, or "entomophagy," has evoked a wide range of feelings in people. Many psychological hurdles must be overcome before it can become mainstream because it is commonly held that neophobia and revulsion are the primary psychological factors that people use to reject entomophagy. With insects in medicine many illnesses have been treated with insects and insect extracts in folk medicine [261]. However, there are challenges associated with the consumption of insects and their therapeutic uses. Traditional medicine is still widely used in many parts of the world, including India, Korea, China, South America, and Africa. However, the practice of tradiational medicine has received little attention in Western culture and economically developed nations [6]. Zimmer [17] reported claimed that the Maya people have been utilizing maggots for therapeutic purposes for about 1000 years. These larvae consume decaying tissue which serves as a habitat for gangrene-causing bacteria that can cause health problems. In many African countries, there is limited access to modern medicine so traditional medicine, which frequently involves the use of insects, is nonetheless widely practiced in some parts of the continent [8,258].

Differences in entomotherapy between western countries and other regions in the world
Acceptance is still a barrier to the widespread use of insects as a medicinal resource for treating diseases and illnesses, especially in developed countries where most people view insects with distaste [262]. However, traditional medicine practices are widely accepted and documented in Chinese and Korean society, but less is known about similar traditions in Africa [263]. Traditional medicine, which sometimes includes insects, is nevertheless widely practised in parts of Africa where access to modern medicine is limited. This alternate medicine has largely received less attention since the advent of modern medicine, partly because of the baffling directions for various treatments [8,45]. As a result, entomotherapy, where insects are used to treat illness, is sometimes disregarded as superstition in many parts of the world. However, traditional medicine is still used in many parts of the world, such as India, Korea, China, South America, and Africa, despite being less popular in Western culture and economically developed nations [6,264]. It is believed that the general public in South America was more open to the concept of using insects as medicine because they were already using them as food in the past [8]. However, in Europe, therapeutic uses appear to have come before gastronomic ones [26,265]. Stick insects are used for treating calluses, warts and prickling spines in the Naga tribes, but in North Korea, they are considered to contain potent healing powers and are used to cleanse the body and remove stomach upset [266].

Earlier principles of collecting the insects
A review of medical use of insects can at least date back to 2000 years ago when the book Sheng Nong's Herbal Classic described multiple medicinal applications of insects [267]. Till nowadays, only a few species are successfully mass produced [268]. More than 90% of the edible insects are collected from the field [268][269][270].
Insects for medicinal purposes differ from insects as food and feed for nutritional purposes in their exact medical effects requirements. Since the nutrients of insects vary even within species [271], principles of insect wide harvesting may include detail description of the stage, sex, time, location, and process to ensure their medical effects. For example, the B. mori adult used in medicine should be the newly emerged male with wings and legs removed [66]. Cicadidae periostracum should be collected in late summer and early autumn when cicadas newly emerged [66]. The best time to collect Mylabris sp. Beetles is the first month of autumn among the thorns of specific plants (e.g., Sophora sp.) [27]. Rhynchophorus palmarum (L.) (Coleoptera: Curculionidae) larvae collected from the native palm tree Mauritia flexuosa (L.f.) (Arecaceae: Arecaceae) is with the best healing properties [272].
Due to the uncertainty (e.g., quantity and quality across season and location) of wide harvesting, some insects have been domesticated for their commercial value. Insect domestication has at least 7000 years history [270], for example the honeybees and silkworms were domesticated during agricultural development [268]. Besides, crickets, mealworms, and the America cockroaches have been successively reared artificially. For example, a farm in Shandong, China, was reported to produce 20,000 kg of dry cockroaches annually [269]. However, not all the insects can be raised completely in artificial conditions. For example, locusts, wasps, and dragonflies are raised in a semi-domesticated way, which means part of the lifecycle is raised indoor or the nature habitat is manipulated to promote production [269]. Most of the rest of the medicinal insects are then still collected in the wide manually by local farmers.
Alternatively, if the effective ingredients have been identified, producing the specific ingredients rather than the insects would be a promising option. For example, the fermentation extract of mycelia from cultivated of C. sinensis is widely used in commercial sale with similar medical function, which has been an effective substitute of wide collection of infected ghost months, Hepialus armoricanus (Oberthür) (Lepidoptera: Hepialidae) [273].

Need for industrial production to produce large quantities of insect-based medicine
The need for insect-based medicine is increasing (Table 10). The emerged medical issues, for example, the increasing cases of cancer due to aging and antibiotic resistance problems leading to urgent requirements of novel drugs [274,275]. Therefore, medicinal insects, which can be potential sources for novel drug discovery, have gained increasing attention in the past decades due to their well-documented functions (e.g., anti-cancer and antimicrobe) [6]. Moreover, people are paying increasing attention to preventive medicine [276]. The willing of health and healing in daily life resulting in the debate of the concept of "food as medicine" [277]. To promote traditional medicine, World Health Organization (WHO) has established the global center for traditional medicine in India [278].
The increased need for medicinal insects has led to overexploitation resulting in severe insect population crisis and habitat damage. For example, the C. sinensis infected ghost moth larva is an important anti-cancer Chinese medicine resource. However, the geographic distribution is confined, which is only available in soil of Qinghai-Tibet Plateau with 3500-5000 altitudes [273]. Overexploitation has pushed the local ghost moth larva facing extinction [273]. Another example is from the bamboo caterpillar, Omphisa fuscidentalis Hampson (Lepidoptera: Crambidae). The traditional harvesting activity usually cut down the entire bamboo clumps which is destructive [281].
Besides, the variation across season is a major challenge in commercialization of wild harvested insects. For example, in Republic of Congo, the migratory locust, Locusta migratoria (L.) (Orthoptera: Acrididae) is only available in November and December while the Termite is only available from November to next April [279]. Referring to the quality variation, modern research has determined many biotic and abiotic factors associated with quality variation. For example, the antimicrobe effects of honey have been determined to vary by species [282], geographical locations [76], types of flowers [225], and the age of honey [208].
More importantly, wild harvested insects have huge safety concerns. Heavy metal is a big concern nowadays due to civilization pollution. For example, the copper level of the wide harvested Mylabris sp. (Coleoptera: Meloidae), which used as an anti-cancer resource, was once determined reaching ~45 mg/kg resulting in carcinogenic risk [283]. Pathogen contamination is another health risk. For example, pathogens (e.g., Bacillus sp. and Staphylococcus sp.) associated with foodborne disease have been determined in raw edible grasshoppers, Ruspolia differens (Serville) (Orthoptera: Terrigoniidae), in Uganda [284]. Besides, agricultural residues, for example veterinary drugs, antibiotics, and mycotoxins, found in wide harvesting insects become major biohazards in medicinal insect market [280].

Table 10
Factors pull/push towards medicinal insect mass production.
The need for medicinal insect mass production References

Factors pull towards medicinal insect mass production
The need for novel drugs [274,275] The need for preventive medicines [276] The establishment of the WHO Global Center for Traditional Medicine [278]

Factors push towards medicinal insect mass production
Over-exploitation leads to species crisis and habitat destruction [273] Quantity variation [279] Quality variation [76] Safety concerns [280] S.A. Siddiqui et al.

What would mass production of insects look like?
Medicinal insects are only small parts of the beneficial use of insects. Besides bees and silkworms, the mass production of sterile screwworm, Musca macellaria Fabricius (Diptera: Calliphoridae) [285] on artificial diet for bio-control purpose is a milestone in insect mass production [270]. The edible insect has gained significantly increasing attention in the past decade as a nutrient pack for food and feed. Insects in general have higher feed conversion efficiency and lower environmental impacts compared to traditional livestock, which are believed to be one of the key solutions against food crisis [270]. Accordingly, the amount of investment, research, and company work on insect mass production increased significantly [268] after the Food and Agriculture Organization of the United Nations (FAO) recommended insects as food and feed in 2014 [286].
Though the nutrient and environmental requirements differ by species. There are following issues need to be considered before setting up an insect farm (Table 11). To set up a mass production farm is not as easy as a small-scale farm because the high density of insect and the subsequent issues related (e.g., metabolic heat and disease).

Breeding
Now most of the edible insects are obtained by trading and a few are wide-collected and reproduced indoor, which the generic diversity is generally uncleared while the concept of insect breeding for food and feed is new [280]. Domestication is a gene selection process. Attention should be paid to insect industrialization, especially medicinal insects, to avoid inbreeding depression, effective ingredient reduction, and increasing vulnerability to pests and diseases [298]. For example, selection for silkworm cocoon weight trait after four generation resulted in poor survival rates [298].

Feed source
The standard quality and continuous supply of feed is essential for insect mass rearing. Depending on the type of insect, the range of feed sources availability varies. For oligophagous like silkworms, the mass production of mulberries is required traditionally. In order to facilitate the sericulture, artificial diets for silkworms have been particularly developed [299]. Under the scope of edible insect production, omnivorous (e.g., crickets) insects are preferred and huge efforts have been put towards the organic waste stream exploitation and formulation [287,288] to meet the low-eco impact willing in insect farming. Besides feed source exploitation, the nutrient (species, stage, and age dependent) and physical form (mouthpart dependent) requirements [268] should be deeply studied to ensure a healthy and reproductive colony.

Facility
The location, mass and energy/heat balances [289], modelling and simulation [290], logistic [291], and the process-type (e.g., batch and continuous systems) should be carefully considered ahead to ensure environmental control system (e.g., temperature, humidity, and ventilation) meet the insect requirements and the workflow is optimized. Life cycle assessment (LCA) [300] and hazard analysis and critical control points system (HACCP) [301] plus a remote sensing monitoring system would be helpful in dealing with such complex system and towards precision agriculture [302].

Processing
Traditionally, most of the medicinal insects were sun dried and then boiled or fried before consumption [66]. Open and unhygienic drying conditions can cause microbes contamination [303]. Along with the development of edible insect industry, more processing methods were addressed, for example freeze drying, oven-frying, fluidized bed drying, microwave drying [292]. Further processing for protein, lipid, and chitin extraction can be achieved by pressing, ultrasound-assisted extraction, cold atmospheric pressure plasma, and dry fractionation [292]. As an alternative to drying, which is considered as an energy-consuming process, fermentation could be applied to raw insects [304]. While the above process would be enough for edible insects as food and feed, further processing (i.e., refining) may be required for medicinal insects processing to concentrate on the effective ingredients, for example the mass production of Xinmailong requires bioactive fraction extracted from P. americana [305].

Packaging and storage
Lipid oxidation can generate toxic products, which are correlated with inflammatory diseases, cancer, atherosclerosis, and aging [306]. Oxidation is common during processing and storage especially for lipid-rich products like insects [293]. Antioxidants and Table 11 Potential aspects to consider for medicinal insect mass production. vacuum-filling nitrogen packaging were determined to be a good method to avoid storage-phase oxidation [293]. Proper packaging and storage environment can also help in remaining low moisture content to suppress microbe growth [307].

Insect disease
Mass production pushed insects to growth and develop at a high density, which provides optimal conditions for insect disease transmission [294]. For example, the A. domesticus densovirus (AdDNV) has caused mass mortality in cricket farms [308]. Hygiene is essential in insect farming to prevent disease transmission. However, once contaminated, shut down the production line and deeply clean the facility seems to be the only option in many cases [308]. Up to date, little is known about the insect pathogens, therefore a programmed called INSECT DOCTORS has been funded in Europe for insect disease specific research [309].

Other
While the above aspects are more related to technical issues, other challenges (e.g., trained technicians, labors, and regulations) need to be overcome by the whole community (e.g., academia, industry, and the consumer society). For example, to avoid food-borne disease contamination, insect farms should follow some hygiene and sanitation protocol. A detail guide on hygiene practices of insect farming can be found on the website of international platform of insects for food and feed [295]. The guide covers legislative requirements from feed stream preparation to harvesting and processing. In European Union (EU) market, insects are viewed as novel food which must be approved following the Novel Food Regulation (EU) 2015/2283. Regulations on insects as food and feed has been reviewed by Ref. [297]. Regulations [296] though ensure consumers receive a good quality product; it usually takes a long time to come out. Therefore, to mass produce medicinal insects that are documented with specific effects, to synthesize the effect compounds, or to discover medicinal effects among approved edible insects, the discussion remains.

Future perspectives and conclusions
Insects have been widely used as medicinal resources in many parts of the world since ancient times. Insects can be used alone or combination with medicinal plants in the treatment of diseases [39]. The promotion and application of medicinal insects play a key role in all existing disease treatments. Though insects form part of the human diet in many countries and regions of the world, their use for medicinal purposes is often not promoted, and Western practice of entomotherapy seems dominant. A wide variety of insect species from different orders, such as Blattodea, Coleoptera, Hemiptera Hymenoptera, Lepidoptera, Odonata, and Orthoptera, contribute to the treatment of diseases in humans. Nevertheless, clinical trials assessing diseases' treatment through entomotherapy have received little attention than insects and insect-derived products utilized as food and feed. In the form of eggs, larvae/nymphs, adults and their derived products, insects provide alternative medicinal properties to modern medicine, though a few studies have attempted to address this issue in some countries. Even countries that use insects and insect-derived products have focused on a few geographical locations. As a result, global records on insect and insect-derived products for disease control are poorly documented worldwide, especially in Africa. More than 2100 insect species are eaten by humans in a wide variety of regions and countries, but little is known about the possibility of using these edible insects in the study and development of new medications and vaccines to battle disease. As a result, medicinal uses of insects, including treating diseases induced by pollution, microorganisms, allergens, and other higher animals, such as snakes and scorpions, could provide insight into the benefits of insects in treating emerging diseases and illnesses. Understating sustainable methods of rearing insects in medicine is critical for biodiversity conservation and prevention. However, insect farming is a concern regarding environmental issues and safety.
In effect, captive farming of edible insects can offer feed and food for animals and humans, respectively, and provide resources for the pharmaceutical industry to discover drugs for various health-related complications. Specifically, among others, future research should provide proper identification of these medicinal insects using molecular tools and conduct further investigation to verify and assess the viability of utilizing insects in the drug discovery process. Limited information exists on the reservations about entomotherapy as there are about entomophagy. Moreover, a clear understanding of the therapeutic use of insects and insect-derived products between Western countries and other regions worldwide requires further investigations. There is also a need to assess consumer opinions/consumer science on entomotherapy. Progress has been towards using insects for medicinal purposes. However, knowledge about their side effects is generally lacking. The relationship between disease treatment using insects and insect-derived products and allergenic effects in patients should be considered in future studies. While a clinical evaluation of medicinal plants' efficacy and safety have been considered by several researchers, such information on medicinal uses insects is poorly documented. Future works should also investigate knowledge, perception, and willingness to apply and pay for entomotherapy. In addition, implications of using insects and insect-derived products on insect biodiversity conservation, the use of insects for the treatment of animal diseases and the contribution of insects to drug discovery may offer a new direction and solution to emerging diseases. Furthermore, among insects used for therapeutic purposes, some are pests responsible for diseases in plants and humans and others play a role in biological control as predators and pollinators of crops. In view for environment and biodiversity conservation, there is a need to select few samples of these insects in investigations necessary to ecological balance.