Insects have been as traditional medicines (9). In the Roman empire, the use of insects for medical purposes was recorded in Naturalis historiae (4). Most of the insects used were from the Orders Coleoptera, Hymemoptera, Orthoptera, and Hemiptera, and were employed in the treatment of disorders of the skin, digestive, respiratory, reproductive, circulatory, nervous, neuromuscular, and immunological systems as well as other diseases. Ethnobiological data have been recorded in many parts of the world. For example, in Europe, the oil extracted from the May beetle larvae (Melolontha vulgaris) was applied to wounds (10). At least 50 and 210 insect species in Brazil and Mexico, respectively, have been reported for use for medical purposes (11). In China, the medical use of crude drugs derived from insects was reported in the “herbal” Jingshi Zhenglei Daguang Bencao (A.D.1108) (12). Many insects have been recorded in traditional medicine to exhibit anti-cancer activities. These uses include use of Bombyx mori and Apis mellifera for lung cancer, Tabanus mandarinus (Chinese horse fly) and Gryllotalpa unispina (giant mole cricket) for liver cancer, Cyclopelta parva (dadap bug) for esophageal cancer, Hueckys sanguea (red lady bug) for skin cancer, Blatta orientalis (oriental cockroach) for renal cancer, and Cryptotympana japonensis (black cicada) for thyroid cancer (13).

Members of Coleoptera (e.g. the Palm beetle (Pachymerus nucleorum), scarab (Strategus aloeus), scarab (Megasona acaeon), and Blister beetle (Lytta versicatoria)) have been used for treatment of earaches, as aphrodisiacs, and to treat urinary disorders (14-17). Hemiptera (e.g. Hyechys sanguinea) have been used to treat migraine and ear infections (18). Orthoptera (e.g. the grasshopper (Tropidacris sp.), crickets (Brachytrupes sp.), and mole cricket (Gryllus assimilis)) have been used to treat skin diseases, defective mental development, and urine retention (4, 17, 19).

In Hymenoptera, wasps, stingless bees, and honey bees have been used as traditional medicine. One of the most well-known insects in this group are bees, which have also been used extensively in folk medicine. In Nepal, bee pollen has been used as a tonic for the elderly (5). Propolis, a plant resin collected by honey bees, is also used as an antiseptic and anti-inflammatory agent in the treatment of wounds and burns. Propolis is a resinous material that bees collect from plant exudates. Bees use these materials to block holes and cracks, as glue to repair combs, make the entrance to hives easier to defend by narrowing the hive entrance, and to embalm dead organisms inside their hives. Propolis has been used in various pharmaceutical products due to its therapeutic properties, such as antimicrobial and antioxidant activities, in both folk and modern medicine used both externally and internally. The hives of stingless bees and European honey bees (A. mellifera) are good sources of propolis (6).

Royal jelly, a bee larval food provided by young nurse bees, is used to treat asthma, anorexia, gastrointestinal ulcers, arteriosclerosis, anemia, hypotension or hypertension, anorexia, gastrointestinal ulcers, and postmenopausal symptoms (9, 20). Moreover, the venom of honeybees has been used to ameliorate the symptoms of inflammatory and autoimmune disorders, including multiple sclerosis (MS), arthritis, rheumatism, chronic pain, neurological diseases, asthma, and dermatological conditions (21). Bee venom was used in ancient Greece for the anti-arthritic properties of apitoxin, which enhances blood flow to ischemic regions. The application of bee stings in treatment of human disease is known as “apipuncture”. Similarly, other insect venoms such as ant venom and wasp venom have been recorded for medicinal use such as treatment of arthritis (22-23).

The order Orthoptera has also been traditionally used for treatment of human disorders, for example, in Africa, powder of dried grasshoppers has been used to alleviate the pain of severe headaches (24). The mole cricket, Gryllotalpa africana, has been used in Korean traditional medicine for retention of urine, urolithiasis, edema, lymphangitis and furuncles (25). In Latin America, the house cricket, Acheta domesticus, was used for the treatment of scabies, asthma, eczema, lithiasis, earache, oliguresis, rheumatism, urine retention, urinary incontinence and ophthalmological problems (26).

Some insects of the order Hemiptera, are known to have medicinal values. For example, the stinkbug (Encosternum delegorguei) in Zimbabwe and South Africa decrease hypertension and have been used to cure asthma and heart diseases (27). The edible Chinese stinkbug, Aspongopus chinensis, has also been employed to relieve pain, and to treat nephropathy and kidney disease in China (28). The bedbug (Cimex lectularius and C. hemipterus) was employed in the treatment of urinary disorders, epilepsy, piles, alopecia, headache, constipation, ulcer, arthritis, hair loss, snake bites and to stop somnolence (29).

Besides the four orders described above, the silkworm (B. mori L., 1758) which is a member of Lepidoptera, has been used in Chinese traditional medicine for at least three thousand years (13) and the larvae of certain flies have been employed for centuries as beneficial agents to heal infected wounds (30).

Even though in some cases, the scientific validity of use has been established, nevertheless, the pharmacological significance of insects, particularly the efficacy of insect-based medicines, has been questioned. Yet, there is increasing interest in demonstrating the scientific validity of medical properties of insects and to prove the pharmaceutical properties of natural products in mice, rats, and, recently, in fruit flies (31).

More than 50 species of known insects are edible. The most common insects consumed in Asian countries are locusts, beetles, crickets, giant water bugs, cicada, ant eggs, silkworm pupae, and bamboo caterpillars. The global population is expected to reach 9 billion in 2050; therefore, a safe, clean, and nutritious food will be urgently needed. Insects are promoted as alternative sustainable source of human food and animal feed worldwide. Insect farming is regarded as environmentally friendly due to their less waste production, less land and water requirement, smaller energy input, and low greenhouse gas emissions, resulting in a lower environmental footprint. We previously reported that these insects are a good source of protein and fiber (Table 1). Most insects contain approximately 60% protein (32) including essential amino acids, such as isoleucine, leucine, lysine, methionine, and phenylalanine, which are suitable for human consumption (Table 2). Insects, therefore, have been proposed as a new source of alternative protein in the future. Insects are also known to be a good source of lipids, particularly in their larval and nymphal stages. Our preliminary results of a nutritional study of edible insect in Thailand found that the Bamboo worm (Omphisa fuscidentalis) consists of 56.89% lipids and provides 778 kcal/100 g (Table 1). Insect lipids are composed of polyunsaturated fatty acids, of which major essential fatty acids are linoleic and α-linolenic acids. In addition, insects contain other nutritive elements such as vitamins and mineral (33).

The insect farming industry has been promoted as an alternative sustainable food source due to an increasing demand of consumers in recent years. The production of honey from A. mellifera and A. cerana for human consumption as well as the silk natural textile production from silkworm are allowed to be the most striking achievement of insect industries. These insects may be domesticated; however, cricket farming has recently become more popular, particularly in European markets. In the European Union, insects that may be used as food are the yellow mealworm (Tenebrio molitor), lesser mealworm (Alphitobius diaperinus), tropical banded cricket (G. sigillatus), and migratory locust (Locusta migratoria) (32, 34). New legislation in Europe on insect food has been in effect since January 2018 and the scientific evidence are required in terms of food safety (e.g. microbial contamination). In the US and Canada, edible insects are regarded as food, and, thus, have to comply with food standards. Since edible insects have traditionally been consumed in Asia, they are widely sold in markets.

Since honey bees and silkworms have contributed to the development of an industry that uses insects to produce food, more scientific information has been accumulated for them than for other insect species. Edible insects with their experimentally demonstrated pharmacological properties are listed in Table 3. Their pharmacological activities, including antioxidant, antimicrobial, anti-cancer, and anti-inflammatory effects, have been examined in various experiments; for example, silk protein from silkworms has been shown to possess anti-microbial properties, while peptides from the tropical house cricket exert both antioxidant and anti-inflammatory effects. The bush cricket (Brachytrupes orientalis) is a popular edible insect in North East India and its extract exhibits antioxidant activities (35). Peptides of the wax moth (Galleria mellonela), yellow mealworm (T. molitor), and silkworm (Bombyx mori) were shown to inhibit angiotensin-converting enzyme (ACE) activity in vitro, causing blood vessels to constrict (36). Hence, these edible insects may be a source of health-promoting food for the treatment of cardiovascular diseases.

Honey, the most consumed product derived from insects, contains many active constituents and antioxidants, such as polyphenols (37). Polyphenols are phytochemicals, a generic form for the several thousands of plant-based molecules with antioxidant activities. Important honey polyphenols, such as kaempferol, quercetin, galangin, chrysin, gallic acid, ellagic acid, benzoic acid, and caffeic acid, are derived from floral sources (38). Honey phenols exhibit many biological activities that include antibacterial and anti-inflammatory activities as well as antioxidative stress activity. They have also been shown to promote wound healing and prevent gastric ulcers. The antimicrobial properties of honey are derived from hydrogen peroxide produced by glucose oxidase, an enzyme secreted from the hypopharyngeal gland of honey bees and a non-peroxide substance derived from plants. For example, methylglyoxal from Manuka flowers has been shown to contribute to the non-peroxide properties of Manuka honey. Honey is used to promote wound healing based on its osmotic properties, moisturize wounds, reduce maceration, and inhibit fibrin-adhering eschar to wounds that may impair tissue repair (39). Honey is also used to treat infectious diseases, skin conditions, gastrointestinal disorders, and allergic rhinitis. In patients with gastroenteritis, honey (50 ml/l electrolyte-glucose solution) safely reduced the duration of diarrhea by two days from that with a standard solution without honey (40). The chemical and biomedical properties of honey are influenced by plant sources. In Thailand, various types of honey are produced and consumed, such as longan, coffee, lychee, sunflower, and wild honey. Pattamayutanon et al. (41) reported that coffee honey produced by A. cerana exhibited strong antioxidant activity (IC₅₀ = 1.788 ± 0.329 mg/mL). It had the lowest IC50, reflecting its strong free-radical reduction activity, and the highest phenolic (1308.62 ± 27.83 mgGAE/kg) and flavonoid contents (0.152 ± 0.015 mgQE/g). The volatiles from coffee honey produced by A. cerana are 2-furanmethanol, butyryl lactone, phenylmethanol, anisaldehyde, anise alcohol, and 3,4,5-trimethyl-phenol. Besides their influence on the aroma of honey, the type and proportion of volatiles in honey affect its therapeutic properties, including antioxidant, antibacterial, and even immunomodulatory activities (42).

Propolis is composed of pharmacologically active molecules, such as polyphenols, sesquiterpene quinones, coumarins, steroids, amino acids, and inorganic compounds. It exhibits antimicrobial activities against various microorganisms, including bacteria, protozoa, fungi, and viruses. The presence of polyphenols in propolis contributes to its pharmacological and biological properties. Brazil propolis is well known because it is rich in flavonoids, prenylated derivatives of p-coumaric acids, lignans, and terpenoids (43). Propolis has also been reported to suppress cancer cell growth (44-46). Tetragonula laviceps is one of the stingless bee species that is commonly kept for commercial purposes in Thailand and South East Asia. Based on taxonomic markers, T. laeviceps propolis exhibited the highest antimicrobial activity and is composed of prenylated xanthones (e.g. α-mangostin, mangostanin, and ϒ-mangostin), which have been identified as major secondary metabolites of mangosteen (Garcinia magostana), a pericarp found in India, Myanmar, Malaysia, the Philippines, Sri Lanka, and Thailand (47). The antibacterial activity of T. laeviceps against Staphylococcus epidermidis, a skin pathogen, confirmed its use in traditional medicine. Tetrigona melanoleuca propolis contains dammar, a tri-terpenic resin produced by trees in the family Dipterocarpaceae. Dammar exhibits antiviral activity and is a protective agent against low-density lipoprotein oxidation (48).

Royal jelly, a larval food of honey bees, is rich in nutrients and biological compounds, such as proteins, lipids, and vitamins. The main biologically active compound is 10-hydroxy-trans-2-decenoic acid (10-HDA), which has been reported to exhibit anticancer activity (49). Antimicrobial peptides, such as royalactin and royalisin, are also present in royal jelly (50, 51).

Bee venom contains immunoreactive and neuroactive peptides, enzymes, glucose, fructose, and water (52). Melittin, a major component of bee venom peptides possesses anti-inflammatory, antibacterial, and antifungal properties and also exerts cytotoxic effects against cancer cells (53). Other peptides in bee venom (apamin, adolapin, mast cell degranulation peptide, and phospholipase A2) also possess anti-inflammatory properties (54-57). Hyaluronidase in bee venom has been shown to increase capillary permeability (58). When eight different types of cancer cell lines were treated with bee venom in vitro, the findings obtained showed dose-dependent growth inhibition in all cell lines, with the highest rate of cell death being observed in the HEPG2 (liver cancer), A549 (lung cancer), and HEP-2C (larynx cancer) cell lines, and the lowest in the HCT116 cell line (colon cancer) (59).

Even though some of the information on the bioactivity of edible insects and their products are currently available, the effects of edible insect peptides and their products on small animals need to continue being investigated for further development (34). Honey bee products are the most studied insect products in animal models. Besides in vitro research on antimicrobial and antioxidant activities, Malaysian Tualang honey collected from the giant honey bee (Apis dorsata) has been examined and reported to exert potentially protective effects against chronic cerebral hypofusion-induced neurodegeneration by reducing neuronal loss and inhibiting neural death in the hippocampus of rats (60). Neurodegenerative disorders affect the neurons of the nervous system (dysfunction or death of nerve cells), resulting in the loss of memory, inability for self-care, loss of communication ability, and personality changes, leading to difficulties in social functions. Commonly known neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), MS, and stroke, are caused by the aging process in addition to increased oxidative stress; therefore, the antioxidant properties of bee products and edible insects have the potential to block this process via dietary intake. The consumption of antioxidant foods has been proposed to attenuate oxidative damage, improve cognitive performance, and slow down the deterioration in memory and learning associated with aging. Dietary phenols in honey have also been reported to prevent neurodegenerative diseases. Luteolin, a flavonoid found in honey, exhibited neuroprotective activity against microglia-induced neuronal cell death and promoted spatial working memory by preventing microglia-associated inflammation in the hippocampus of aged rats (61). A previous study also reported that honey reduced neuroinflammation and caspase-3 activity after kainic acid (KA)-induced status epilepticus in rats (62). Quercetin, kaempferol, ferulic acid, chrysin, and chlorogenic acid in honey have been shown to exhibit neuroprotective activity in rat models (63-70). Caffeic acid, another important phenolic acid and antioxidant, which is found in honey, suppressed neuroinflammation in the brain tissues of mice (71). Tualang honey has been shown to improve short- and long-term memory as well as the neuronal proliferation of hippocampal regions in rats (72). Similarly, the consumption of honey with a high antioxidant content decreased deteriorations in brain function during aging and, thus, reduced anxiety and improved spatial memory in rats (73).

Gastric ulcers are a major issue worldwide and there is, as of yet, no effective treatment. Manuka honey was previously shown to significantly reduce the ulcer index and maintain the glycoprotein content, and these effects were attributed to its antioxidant properties. It also reduced mucosal myeloperoxidase activity, lipid peroxidation, and the levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) to lower than those in the untreated control group. In addition, rats treated with Manuka honey showed a normalized cell cycle distribution and significantly reduced apoptosis in the gastric mucosa. These findings demonstrated that Manuka honey is effective in the treatment of chronic ulcers and preservation of mucosal glycoproteins (8).

Honey has been reported to exert protective effects against metabolic syndromes (74). Metabolic syndromes (e.g. cardiovascular disease, hypertension, and diabetes) are linked to lifestyle choices. The anti-obesity effects of honey were previously reported in a rat model (75, 76). The hypoglycemic effects of stingless bee honey and giant honey bee honey have been tested in rats (77-79). Royal jelly was found to ameliorate diet-induced obesity and glucose intolerance in mice (80). Furthermore, Seo et al. showed that the daily intake of yellow mealworms attenuated weight gain in obese mice by increasing lipid accumulation and triglyceride levels in adipocytes (81).

Brazilian green propolis contains prenylated phenylpropanoids and flavonoids and exhibits antioxidative and anti-inflammatory activities. Furthermore, its extract suppressed acetaminophen-induced hepatocellular necrosis by modulating cytokine expression in rats (82). Luteolin is a flavonoid found in honey that exhibited neuroprotective activity against microglia-induced neuronal cell death and enhanced spatial working memory by preventing microglia-associated inflammation in the hippocampus of aged rats (83). Among flavonols (quercetin, kaempferol, galangin, fisetin, and myricetin), flavones (apigenin, acacetin, chrysin, luteolin, genkwanin, wogonin, and tricetin), phenolic acids (caffeic acids), and flavanones (hesperidin), quercetin has been shown to enhance the apoptotic activities of anti-CD95 and rTRAIL (recombinant tumor necrosis factor-related apoptosis-inducing ligand) in acute lymphocytic leukemia (84). Apigenin and acacetin not only induce caspase-dependent apoptosis in human leukemia cells in vitro, the former also induced the apoptosis-mediated inhibition of U937 leukemic cell xenografts in mice (85).

In an in vivo study, the administration of bee venom to carcinoma-bearing rats significantly reduced their body weight, ascites tumor volume, packed cell volume, viable tumor cell numbers, and tumor cell count and increased their mean survival time. These findings suggest that the bee venom studied is applicable as an effective anticancer agent (59). Bee venom also exerts neuroprotective effects. For example, when bee venom phospholipase A2 (PLA2) was injected into a mouse model of PD, the second most common neurodegenerative disorder, it attenuated neurotoxicity and enhanced motor functions (86). Melittin in bee venom reduced the expression of inflammatory proteins in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). These findings suggest that melittin has potential as an agent to regulate the immune system in organs with the loss of motor neurons caused by ALS (87).

The Drosophila melanogaster genome project was completed in 2000. Approximately 75% of human disease-causing genes have functional orthologues in Drosophila. Drosophila is a good model organism because it has a short life span and produces a large number of offspring. It has been used to investigate degenerative diseases related to the nervous system, such as neurodegradation, AD, PD, sleep disorders, and aging. Drosophila has also been used as an animal model of neurodegradation, AD, PD, sleep disorders, ALS, and cancer (31). However, limited information is currently available on edible insects and insect-derived products tested using Drosophila models. When Drosophila was fed the boiled and freeze-dried powder of silkworms (B. mori), their life span increased and the symptoms of rotenone-induced PD were attenuated (88). Yamanashi et al. reported that when flies were fed freeze-dried royal jelly, royal jelly influenced the adult physiology via a shorter developmental time, prolonged longevity, and increased female fecundity (89). These findings suggest that royal jelly maintains certain bioactivities in multicellular organisms and Drosophila mutants may be a useful model to study lifestyle- and age-related diseases. A Drosophila model of the knockdown of ubiquilin, which induces severe morphological defects in neuromuscular junctions (NMJs), has been used to examine edible insect proteins and honey bee products. When Drosophila mutants were fed food supplemented with coffee honey, bee venom, and wasp protein, the number of boutons was significantly higher in the three treatment groups than in the control. These findings suggest that these insect products have neuroprotective properties. Furthermore, the anti-inflammatory activities of coffee honey, royal jelly, and melittin were demonstrated in the Drosophila model.