A Review of Kahu (Lactuca sativa Linn.): An Important Drug of Unani System of Medicine

Introduction

The Unani System of Medicine (USM) is one of the oldest systems of traditional medicine, based on Hippocrates theories of temperament (Mizaj) and humors (Akhlat).¹ The basic principle of treatment is contrary therapy (Ilaj-bil-zid). Pharmacotherapy is concerned with three natural sources of drug (Mawaleed-e-salasa), i.e. plants, animals, and minerals, in either single or multiple dosage forms.² According to the WHO, traditional medicines are used by more than 80% of the world's population, primarily drugs of plant origin (Adviya Nabatiya).³ Lactuca is a vast genus of annual and perennial herbs with about 25 species, all of which produce milky latex.⁴ In USM, two cultivars are popularly recognized as Kahu: Bustani Kahu/ Cultivated lettuce/ Garden lettuce (Lactuca sativa Linn. or Lactuca scariola L.) and Sahrai Kahu/ Kahu Barri/ Wild lettuce (Lactuca virosa L.).^4,5 The presence of two sesquiterpene lactones named lactucarium and lettuce opium in the white liquid (latex) contributes to the sedative properties.⁵ These plants are members of the Compositae family, which includes sunflowers, asters, and daisies (Asteraceae).⁴ Although wild lettuce is more potent than cultivated lettuce,^2,6 Unani physicians only utilize the latter as a therapeutic medication.^2,7 Smallpox may be prevented by eating lettuce, according to American settlers, while typhoid could be treated by eating lettuce seeds, according to Iranian academics.⁸ The ancient Egyptians believed lettuce to be a sign of sexual prowess and reproduction in women, whereas the ancient Greeks and Romans believed it to be a source of male impotence; therefore it was offered at funerals (owing to its involvement in the myth of Adonis' death).^5,7 Furthermore, British ladies in the nineteenth century believed that it would result in infertility and sterility.⁸

Lactuca sativa Linn., which is frequently mentioned by USM scholars in their classical book, has a long history of usage in single and combination form in disorders of diverse body systems. Since there is paucity of literature on this significant medicine, an initiative has been undertaken to consolidate all accessible material on Lactuca sativa Linn. in order to highlight the drug's therapeutic potential.

Materials and Methods

A Bibliographic search was carried out to collect the available information on Kahu. The information was collected from different books of Unani literature and conventional medical science. Standard Unani Medical Terminology was used to describe the appropriate Unani terminologies. The wealth of India and different indexed journals were consulted for morphological and therapeutic description. Contemporary reference books, relevant articles, periodicals, peer reviewed indexed journals and other published works available on PubMed, Science Direct, Google scholar and Scopus were used to retrieve online literature.

Results and Discussion

Synonyms

L. capitata (L.) i; L. crispa (L.) Roth; L. laciniata Roth; L. palmata Willd. ⁹

Taxonomic classification

Kingdom: Plantae; Family: Asteraceae; Genus: Lactuca; Species: Lactuca sativa.⁸

Vernaculars

Arabic: Bazr-ul-khas,^5,9,10 Khas, ^9,10,11 Al-Khas nabat; ⁹ English: Lettuce,^8,12 Lettouce, Prickly Lettuce; ¹¹ Greek: Marouli;¹¹ Hindi: Kahu,^2,5 Salad, ^4,5 Kahu-khaskabija; ⁹ Persian: Kahu,^5,12 Tukhm-e-Kahu,^5,2,10,11 Khurasani Khoo, Keehar,² khas; ⁹ Tamil: Salattu, ⁵ Shallatull-virai; ⁹ Unani: Jariqus, Waidiqus, ² Thredas; ⁷ Urdu: Kahu. ^5,9.11

Morphological description

Wild Kahu features broad, long, rigid leaves,^2,7,12 delicate branches, white flowers with white, small, elongated, tasteless seeds, and milky secretion of bitter flavor^2,12 known as lactucarium or latex (Afyun Kahu) because it resembles black opium seeds milk (Khashkhash).^2,7,12-14 Cultivated Kahu plants can be segregated into two groups. The first has broad, smooth, sweet, delicate leaves, grows to a height of 455 cm, has thin branches, and white blossoms, as well as smooth, sweet, white, and thin seeds. While the seed grows, milk is produced, and the leaves become bitter. Farangstani is the second type, which is further separated into two categories. The first features green, delicate, and delicious leaves, while the second has pointy bluish tint leaves and black seeds. As it grows to its full size, the power of its milk surpasses the potency of wild latex.^2,7,14

Habitat

The garden lettuce is grown in the warmer temperate parts of Western Asia, including Eastern Mediterranean, and descended from L. scariola L., while prickly lettuce is found wild in the Himalayas and north temperate regions of the old world.⁴ It is also grown in Iran, Arab, Rome, Europe, etc. in spring season and in India & Bangladesh during cold weather.^2,11,15 However, it can be grown anytime during spring or early summer.⁴ It is grown as a culinary food in many parts of India^5,6 and Persia,⁵ and the lettuce grown from English seeds in India outperforms those grown in Persia.⁹ From planting to harvesting, lettuce can take anywhere between 65 to 130 days, depending on the type and time of year.⁸

Description of Different Parts of the Kahu

Latex (Afyun kahu)

Lactucarium is a brown viscid substance generated by evaporating the fluid that runs when wild lettuce stems or any other part of the plant is wounded.⁵

Temperament: Cold and dry 4^th degree¹⁰

Dose: 30 mg - 125 mg¹⁰

Therapeutic uses: Wild latex is more effective than cultivated, according to Shaikh, who claims that the wild type's potency is due to its resemblance to black opium.^{2,7,10,12,13,14} In syrup and tablet form, it relieves dry cough⁷ and treats corneal ulcers, corneal fistulas, scorpion bites,^2,7,12,14 and 1.75 mL with vinegar and water acts as a purgative for liquid chyle.^7,10,12,16 Dried juice or extract has been used as an emmenagogue,^2,7 sedative, and soporific since the Roman Empire,⁹ and unlike opium, it does not cause constipation, digestive disorders, or lethargy.^2,7,12,13,14 In France, the Lactucarium has been utilized as an opium substitute in cough syrups.⁹

Lettuce leaves (Berg-e-kahu)

Temperament: Cold and wet 2^nd degree, but less moisture (Rutubat) in leaves of black seed plant ^2,5,10,13,14 or wild leaves have less moisture than cultivated or^2,7 cold 2^nd degree & moist.¹²

Dose: Lettuce water (Aab berg-e-kahu) 105 mL² / 80-96 mL⁷ / 25-100 mL⁷ / 1-500 mL²

Therapeutic action: Resolvent (Muhallili-i-waram haa'r), Deobstruents (Mufattih sudad), ^6,10 haemopoietic (Muwallid-i-dam),^{2,7,11,12,13,14} blood purifier (Musaffi-i-dam),⁷ laxative (Mulayyin), refrigerant (Mubarrid), diuretic (Mudirr-i-baul),^2,7,12 antipyretic (Musakkin-i-hrarat), Galactopoietic (Muwallid-i-laban/ galactogogue),^{2,11,13,14,16} Nutritive (Mughadhdhi),^2,7,13,14 Anti-thirst (Musakkin-i-atash) activity & cooling effect (Musakkin hiddat safra w josh khoon) of bile & blood,^6,7,12 increases the viscosity of pneuma (Mughallizˌ-i-ruˉh), Anesthetic (Mukhaddir),^2,7,13 Hypnotic (Munawwim),^{2,7,11,12,13,14}, & removes the dryness of bile and black bile (Dafi yabusat safra w sawda).^11,17

Therapeutic uses: For people with a hot temperament, the fresh plant is the finest medication.^2,7 Sheikh claimed that unripe lettuce (Kahu khaam) or its decoction has a hypnotic effect due to rise in the viscosity of Pneuma (Gilzat rooh)¹³ and relieves sleeplessness,^2,7,13,14 particularly in the elderly.¹² It is also beneficial in delirium due to its cooling impact.¹³ Lettuce produces good quality humor^7,12 or blood (hematinic)^2,7,12,14 than other vegetables, is easily digestible, and is the best stomach meal.^2,12,14 It becomes more nutritious as it ripens, as all viscous fluid is dissipated,^2,12,13 and it also aids in the generation of black bile.² Because of its characteristics (Khasiyat), it is utilized as a disinfectant in cases of air pollution and water contamination.^2,7,12,13 Chewing leaves while drinking alcohol is useful in practically all addiction difficulties because it cools the vapors and freezes them. Along with vinegar, it is good for bilious headache (Sawda safrawi rihi) and with rose oil (Roghan-i-gul), it is good for sunburn headaches.^2,7,12,13,14 Locally, it helps with joint discomfort,^2,14 headaches, heat conjunctivitis^,2 and inflammation^2,7,12,16 of small and mild conditions.^2,14 A paste made from lettuce leaves water (Aab Kahu) and barley flour (Aarad Jau) slows the progression of hot eye inflammation.^2,12 According to Sheikh, the surface of leaves contain hot and light elements that have the ability to dissolve or disintegrate thrombus/obstacle (Sudda) like chicorium when employed in its natural state.² Shareh Geelani claims that it helps in jaundice,^2,5 while Sahab Makhzan reported its laxative and diuretic properties due to its Deobstruents potency.^2,7 Powder (Zarur) of burned Kahu (Sokhta Kahu) is good for stomatitis, scorpion bites, hair loss,^2,7,10,12,16 and as a gargle in glossitis.^2,7 Lettuce is primarily used by Europeans as a salad plant and by Iranians as food.^4,7,11 Its oral use improves appetite,^2,11,12,14 purifies blood, and cures biliousness, burning sensation, nose trouble, bronchitis, and cough due to heart disease. It is also used in scabies, leukoderma, liver diseases,¹¹ sinusitis,^2,7 leprosy, mania, urinary tract ulcers.^2,6,10 Lettuce water has the therapeutic potential to heal hot headache and meningitis.¹⁶

Side effect: Kahu leaves has negative effect on the reproductive organs^2,7,10 and the gut.¹² It causes emphysema or diphtheria in tuberculosis and asthmatics and to counteract this, honey water (Ma'al-'asal) can be used as an emetic, Hyssopus officinalis (Zoofa) decoction can be used as an expectorant and detergent, and Majun rabu as an antidote.^2,7,12 It leads to dementia,^7,10 memory loss,⁷ vision problems,^7,12,14,16 and paralysis.¹² Recurring use causes blindness and as a preventative measure for this, Habb-e-Qoqaya is advised to be taken orally and fennel water must be applied topically (Aab Badiyan).^2,7,12 It has been reported that consuming lettuce causes hepato-pulmonary masses.¹⁷ Kahu that has been washed creates more flatulence than unwashed Kahu. ^2,7,10,12,14

Corrective: For flatulence, use Black cumin seed (Zeera Siyah),⁷ Mentha (Podina),⁶ Celery seeds (Karafs),^2,7,16 Halela murabba,¹⁷ and Beet root (Shaljam).^2,7

Substitute: Cultivated Chicories (Kasni Bustani)^2,7,16 and Purslane leaves water (Aab Berg Khurfa).¹⁰

Formulation: Qurs-e-musallas, Qurs-e-tabasheer kafoori, & Roghan-e-laboob sab’a. ^6,10

Lettuce seed (Tukhm-e-kahu)

Temperament: The white seed is cold and dry 2^nd degree^9,10 /cold and dry 3^rd degree¹⁶ /cold 1^st & dry 2^nd degree /cold 1^st & dry 2^nd & the black seed is hot and dry 2^nd or 3^rd degree.⁷

Time of collection: The best seed comes from plants that are sown at the end of October 4 or throughout the fruiting season, when the seeds mature.⁶

Preservation & storage: Seeds quickly lose viability in warm, humid environments. They should be kept in a cool, dry location.^4,6

Dose: Various doses, such as white seed powder 500 mg-125 gm orally (as a sedative)¹⁸/ 3-5 gm⁶,11/ 6-12 gm⁷ / 24-48 gm, are described in various books.^6,10

Therapeutic action: Anesthetic (Mukhaddir), hypnotic (Munawwim),^2,7,12,16,19 anodyne (Musakkin-i-alam), diuretic (Mudirr-i-baul),^6,7,9 expectorant (Munaffit) similar to opium,^9,10 demulcent (Mulattif), refrigerant (Mubarrid),^5,12 inflammation fluid concoctive (Mundij-i-waram),⁷ anti-thirst (Musakkin-i-atash).^7,10,12

Therapeutic uses: Seed powder is used in the treatment of fever, active inflammation, cough,⁶ asthma, pertussis and insomnia, wakefulness due to mental overwork, rheumatism, lunacy,⁹ and gonorrhea.⁶ With semen desiccating action (Mujaffif-i-mani & Mughallid-i-mani),^{2,7,9,10,12,14,16} powder at a dose of 7 gm² and decoction is useful in excessive nocturnal emission & dribbling micturition (Na'fi kasrat ehtelam & Taqteer-i-baul),^{2,7,9,10,12,14,16} while recurrent use reduces the sexual desire (shahwat jama).^2,7,10,12,14 A decoction is used as a demulcent in the treatment of bronchitis^,7,10 especially chronic bronchitis,⁹ coryza, and sinusitis,⁷ and to relieve excessive thirst and stomach heat.9 In chronic bronchitis, a dose of 3.543 - 7.087 gm of concoction is helpful. The poultice of lettuce has a soothing effect on a sore ulcer.^9,11 In Ilaj-ul-gurba, the inhalation of lettuce, coriander, and catechu has been prescribed for delirium. Inhale these after mixing them with vinegar. In the same way, a confection made of mucilage extracted by soaking two parts poppy seeds in water for every one-part lettuce seed sweetened with adequate sugar is indicated for insomnia. Lettuce, when combined with hot water, is used to treat dyspepsia and liver problems. Because of its calming properties, the seeds paste is beneficial for headaches,^2,7,12 prevents hair loss^2,7,11,12 and is effective in scorpion bite.^2,7,12

Side effect: Seeds have a non-desired effect on the reproductive organs^2,26 and stomach,⁹ and can also cause visual weakness^12,13 and amnesia (Nisyan).⁷

Corrective: Mastic (Mastagi)^2,7,12 & honey.¹⁹

Substitute: Opium seeds (Khashkhash), & Dragon seeds (Dammul akhwain).^2,7

Formulation: Raughan-e-Kahu.⁶

Lettuce oil (Raughan-e-kahu)

Method of preparation (Dohnul khas): To make juice, clean seeds and crush them with purified water in a grinder, then boil two parts seed water (Sheera Tukhm-e-kahu) with equal amount of sesame oil (Raughan-e-Kunjud)^15,20 or one-part almond oil (Raughan-e-badam)⁷ at a low temperature for about five and half hours to evaporate the purified water. Filter the entire contents through a muslin cloth while it is still hot and set the filtrate aside to cool.¹⁵

Storage: Store in a cool and dry place in a firmly sealed container away from light and moisture.¹⁵

Temperament: Cold & moist 2^nd 16 or cold & moist.⁶

Dose: Large amounts^11,14

Mode of administration: External use only.¹⁵

Therapeutic action: Oil produces moisture in the brain (Murattib-i-dimagh). Hypnotic (Munawwim), relaxant (Musakkin)^,2,7,15,19 refrigerant (Mubarrid), and demulcent (Mulayyin-i-waram haa'r) properties are all found in oil.^2,7,19

Therapeutic uses: The oil has a strong flavor that is beneficial to the brain,¹¹ in rigid inflammation (Muhallil-i-Salabat), melancholia (Malinkhooliya), epilepsy (Sura Yabis),^2,7,15 neurological illnesses of the hot kind,⁷ and euphoria⁹ in all locally effective (Da'fi khumar).

Side effect: Oil causes amnesia and visual weakening in people with a chilly temperament, as well as negative effects in the reproductive organ.¹⁹

Corrective: Honey¹⁹ & almond oil (Raughan-e-Badam).⁷

Substitute: Pumpkin oil (Raughan Maghz Tukhm Kaddu).⁷

Kajal raughan-e-kahu

Temperament: Hot & Dry in 1^st degree.¹⁹

Dose: Adequate quantity.¹⁹

Therapeutic action: Relief from burning eye (Musakkin sozish chashm).¹⁹

Therapeutic use: Burning eye.¹⁹

Side effect: Exaggerates cold diseases.19 Corrective: Kajal of Raughan-i-Badam Shireen (sweet Almond oil).¹⁹

Contraindication of Kahu

Lettuce is harmful to people with pyothorax and asthma because it induces diphtheria by drying the pus and fluid,^2,7,12 as well as people with benign prostatic hyperplasia (BPH) and glaucoma. Excessive use, especially during lactation and pregnancy, should be avoided due to a lack of toxicological evidence and the possibility of allergic reactions.⁹

Interaction of Kahu

The vitamin K in lettuce counteracts the action of Warfarin, which can have dangerous side effects.²⁰

Phytoconstituents of Kahu

Lettuce is a good source of vitamin K and vitamin A, as well as folate and iron.⁸ Organic constituents of lettuce seeds include glycosides, steroids, phenolics, tannins, and resins, whereas inorganic constituents include sodium, potassium, magnesium, iron, copper, and chloride. The sesquiterpene lactones 3-hydroxy-11, 13-dihyrox canthospermolide, 3-14-dihydroxy-11, 13-dihyrocostunolide, hydrolactucin, lactucin, and lacupicrin are found in cultivated leaves.⁷ Among vegetables, Romaine lettuce is high in phytosterol.²¹ Gas chromatography–mass spectrometry (GC-MS) was used to examine 62 components of essential oils, the most prominent of which were n-Hexanol, trans-2-Octen-l-ol, and 2-n-Pentylfuran.²² GC-MS identified oxygenated monoterpenes, sesquiterpenes, hydrocarbons, volatile organic compounds, and their derivatives as pinene, cymene, thymol, durenol, terpinene, thymol acetate, caryophyllene, camphene, and limonene as major constituents of essential oil from fresh and dry lettuce. Other minor chemical elements of lettuce essential oil were extracted and identified, including pinene, terpinolene, linalool, 4-terpineol, terpineol, o-methylthymol, L-alloaromadendrene, and viridiflorene, with the concentration in dried leaves being significantly lower.²³ A soft gelatin capsule containing 1000 mg of pure expressed L. sativa seed oil is available. According to Gas liquid chromatography (GLC), the capsule is mostly composed of oleic acid (61.5%), stearic acid (20.4%), palmitic acid (9.7%), myristic acid (2.8%), cispalmitoleic (1.2%), behenic acid (0.5%), and lignoseric acid (0.3%), with B-sitosterol and B-amryn also present.²⁴

Scientific studies

Toxicity studies

In male albino mice, the LD50 of a hydro alcoholic extract of the aerial part was found to be 4.8 g/kg;^18,25 no neurotoxic effect was observed in cultured PC12 neuron-like cells, and no abnormal behavior or lethality was observed with a methanol/petroleum ether extract of the seed up to 6 g/kg.²⁶ Seed oil has an oral LD50 of 19.75 mL/kg in mice.²⁷

In vitro studies

Green lettuce polyphenols are responsible for J774A's anti-inflammatory and antioxidant properties. Reduced reactive oxygen species, nitric oxide release, and inducible nitric oxide synthetase and cycloxygenase-2 expression in macrophages activated with Escherichia coli lipopolysaccharide (LPS).²⁸ Because of the increased amount of phenolics in the methanolic extract of Lactuca sativa var longifolia leaves, it had much better hydroxyl radical-scavenging action than the aqueous extract. Using a cytopathic effect (CPE) reduction experiment, it was likewise the most efficient extract with the lowest MIC against all gram negative and gram positive bacteria, and both extracts displayed antiviral activity against HCMV and Cox-B3 viruses with IC50 of 200 g/mL.²⁹ The water portion of a green leaf lettuce hydro alcoholic extract at 400 g/mL can protect N2a cells from glucose/serum deprivation (GSD) by reducing intracellular lipid per oxidation, as measured by malondialdehyde (MDA) levels and DNA fragmentation using single cell gel electrophoresis. This research showed that lettuce has a Geno protective impact by inhibiting oxidative stress.³⁰ By using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, the N-butanol fraction and ethyl acetate fraction exhibited the neuroprotective effect by inhibiting the cytotoxic effect of GSD-induced cell death in an in vitro model of brain ischemia.³¹ In another study, cell viability, DNA damage, and proapoptotic or antiapoptotic protein levels were determined as a parameter of neuroprotective activity using MTT, comet, and immunoblotting assays, respectively, with intracellular reactive oxygen species and lipid per oxidation levels measured using a fluorometric method. The lettuce ethyl acetate fraction prevented all GSD-induced neurological alterations by reducing oxidative stress and inhibiting proapoptotic pathways, according to the findings.³² The activation of checkpoint kinase 2 (Chk2), induction of the tumor suppressor p21, and severe down regulation of the proto-oncogene cyclin D1 coincides with the water extract inhibiting the development of HL-60 leukemia cells and MCF-7 breast cancer cells. The ethyl acetate extract caused HL-60 cells to die, which was linked to alpha-tubulin acetylation. For a person of 75 kg, the calculated intake would be 300 g dried L. sativa or 3 kg fresh L. sativa, which is certainly excessive. However, because the antiproliferative effect is water soluble, this amount could be consumed as squash juice or any other liquid form.³³ ACE-inhibitory activity of (S)-malic acid 1′-O-gentiobiosides screened from lettuce using an LC-MS/MS-based in vitro assay that is stable against salivary glycosidase and stomach acid. Through its inhibitory action on one of the GABA degradative enzymes succinic semialdehyde dehydrogenase, the phytol component has the ability to raise GABA levels in the CNS.³⁴ Candida albicans is inhibited by Terpenes and cardenolides in Latex sap of lettuce, as observed by scanning and transmission electron microscopy.³⁵

In vivo studies

Lettuce seed oil improved FSH, LH, and testosterone levels in male rats’ serum due to a high concentration of vitamin E, which plays an important role in hormone production in the pituitary gonadal axis in humans and rats, and reduces insulin resistance by improving endothelial function and lowering oxidative stress. It also has an inhibitory effect on lipid peroxidation in blood cell membranes, as well as free radical quenching activity, as seen by a significant rise in Glutathione (GSH), superoxide dismutase (SOD) and Catalase activity.³⁶ At doses of 100, 150, and 200 mg/ kg BW orally thrice a week for 10 weeks, flavonoids and saponins from ethanolic extract of leaves reduce Thiobarbituric acid reactive substances (TBARS) and nitrite while increasing antioxidant enzymes such as catalase (CAT), peroxidase (POD), Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH). Serum levels of testosterone, LH, FSH, estradiol, prolactin, histology, body weight, and relative testis weight were all restored to near-normal levels by scavenging free radicals in various cells and organs while regulating their activities, which was beneficial in secondary infertility.³⁷ With the presence of triterpenoids, saponins, and simple phenols in the methanol/petroleum ether extract of seed, time and dosedependent anti-inflammatory activity was exhibited in a carrageenan model of inflammation. These constituents may also be responsible for the time and dose-dependent analgesic effect in the formalin test but no analgesic effect was noted in the tail-flick test up to the highest dose used (6 g/kg).²⁶ Because of the presence of simple phenolics, saponins, and triterpenoids, methanolic extract of seed reduced edema production largely from the first hour and during all stages of inflammation. The prostaglandin synthetase enzyme, which may be responsible for analgesic activity is inhibited by flavonoids.³⁸ Seed extract has the shortest immobility time in the forced swimming test, suggesting that it could be used as a CNS antidepressant. In comparison to aspirin, seed extract has anticoagulant action by increasing the coagulation time.³⁹ At 50 mg/kg, hydro-alcoholic and aqueous extracts of seed reduce sperm count and viability. Thirty minutes before the pentobarbital injection, mice were given the hydro alcoholic extract (HAE) of lettuce, as well as its water fraction (WF), ethyl acetate fraction (EAF), and n-butanol fraction (NBF). At a dose of 400 mg/kg, the HAE extended the duration of pentobarbitalinduced sleep. Because of the non-polar agent(s) present in this plant's NBF, it was the only fraction that could improve sleep duration and decrease sleep latency equivalent to those caused by diazepam.²⁵ In mice, a hydro-alcoholic extract of leaves showed substantial anxiolytic properties. In Lactuca sativa-treated mice, increased locomotors activity and time spent in the "open-arm" was measured using the open field test (OFT), elevated plus maze test (EPM), elevated T maze test, and marble burying test. MDA and nitrite levels were also reduced, while catalase and glutathione levels were increased.⁴⁰ The stem of L. sativa exhibited calming effects on toad motor activity and behavior, along with inhibition of striated and smooth muscle contraction in nerve-muscle preparations and lowering heart rate and ventricular contraction in normal and tachycardia. After large doses, electrocardiograms revealed an arrhythmia characterized by significant atrioventricular block, as well as flaccid paralysis. The effects of administering it to the cerebrospinal fluid, lymph sacs, and brain imply that it functions mostly peripherally and does not readily pass the blood-brain barrier by interfering with basic excitatory mechanisms found in muscle and neurological tissues.⁴¹ Lactucin, as well as its derivatives lactucopicrin and 11, 13-dihydrolactucin, are bitter sesquiterpene lactones. In thermal nociception models, lactucopicrin proved to be the most powerful analgesic of the three compounds examined; similar to what was shown with ibuprofen as a conventional medication. In the spontaneous loco motor activity test, lactucin and lactucopicrin also revealed sedative characteristics.⁴² Feeding 20% lettuce to rats for three weeks resulted in a lower LDL/HDL ratio and a significant decrease in hepatic cholesterol levels, as well as enhanced fecal total steroid excretion and reduced dietary cholesterol absorption. Also it improved vitamin E/TG ratio in plasma and limited lipid per oxidation in heart as evidenced by TBARS. In post-prandial experiment, lettuce intake significantly increased both ascorbic acid and alpha-tocopherol plasma levels which contribute to improved plasma antioxidant capacity within 2 h of feeding. Other lipid-soluble antioxidants (lutein and vitamin E) may also improve the plasma antioxidant capacity.⁴³ In Alloxan-induced male diabetic rats, aqueous extract of Hattaraki pallye or prickly lettuce leaves, either acute or sub-chronic supplementation, demonstrated a better glucose tolerance and hypoglycemic management of blood sugar in diabetic rats with or without nickel (II) treatments.⁴⁴ In an in vitro investigation using HepG2 human liver cancer cells, antiproliferative effects were also found to be considerable.⁴⁵ In the midgut of silkworm Bombyx mori larvae treated with ethanolic extracts of B. monniera and L. sativa, a substantial decrease in non-specific esterase (NSE) activity was measured. The findings revealed a strong link between lipid peroxidation-induced oxidative stress and nonspecific esterase activity.⁴⁶

Clinical trials

Lettuce polyphenols convert nitrite to nitrous oxide, which may have a physiologic effect in terms of local intestinal relaxation. The study examined the effects of acute ingestion of fresh and stored lettuce on plasma total antioxidant capacity and antioxidant levels in healthy people, and found that plasma total radical-trapping antioxidant potential (TRAP) was significantly higher than that of modified-atmosphere packaging (MAP) stored lettuce.⁴⁷ Using the Persian version of the "BEARS" pediatric sleep questionnaire before and after the intervention in an randomized controlled double blind study, local application of seed oil containing sesquiterpenes lactone on the forehead and temporal region significantly improved bedtime issues, excessive daytime sleepiness, night awakenings, and problems in regularity and duration of sleep, especially in children, in comparison to placebo oil and clonidine capsule for three weeks.¹⁸ In another prospective randomized clinical trial on 100 pregnant women suffering from insomnia, the Pittsburgh Sleep Quality Index (PSQI) score was considerably higher in patients taking lettuce seeds orally at 1000 mg dose in capsule form daily for two weeks than in those consuming placebo.⁴⁸ In addition, a pilot trial that was conducted in insomniac patients with or without anxiety at a dose of 1,000 mg seed oil for a week exhibited improvements in the modified state-trait anxiety inventory and sleep rating scale scores when compared to placebo.²⁴

Conclusion

Unani scholars argue that lettuce and its many parts, particularly the oil, are beneficial in the treatment of disorders caused by excessive heat, such as headache, burning stomach and bladder, high sexual desire, premature ejaculation, and diseases caused by dryness, such as insomnia. Majority of experimental studies and clinical trials also point to the possibility of such an effect due to its phytoconstituents, although more detailed and extensive research is needed to affirm this.

Conflict of interest

None

Acknowledgement

The authors are grateful to the National Institute of Unani Medicine (NIUM), Bengaluru, library staff for providing classical literature, manuscripts, and other necessary materials on the subject.