A narrative review of the ethnomedicinal usage of Cannabis sativa Linnaeus as traditional phytomedicine by folk medicine practitioners of Bangladesh

Background There is a worldwide interest in the use of Cannabis sativa for biomedicine purposes. Cannabis has ethnomedicinal usage as a natural medicine in Bangladesh and cultivated during the British Empire period for revenues. Objective Folk medicine practitioners (FMPs) from different districts of Bangladesh have been using Cannabis sativa, but until now there have not been any compiled studies particularly regarding this practice. Hence, this review is an effort to retrieve the traditional usage of Cannabis sativa as a phytomedicine from published ethnomedicinal studies. Methods and materials Information was searched by using the search terms “ethnomedicinal Cannabis sativa and Bangladesh”; “Bangladesh cannabaceae and ethnomedicinal survey”; “ganja, bhang and folk medicine Bangladesh”; “tetrahydrocannabinol (THC), cannabinoid and therapeutic, clinical trial”; and “cannabis and pharmacological/biological” and retrieved from ethnobotanical articles available on PubMed, Scopus, Science Direct, and Google Scholar databases. A search of the relevant scientific literature also was conducted to assess the efficacy of the ethnomedicinal usage of Cannabis sativa. Results While reviewing over 200 ethnomedicinal plants’ survey articles, we found that FMPs of Bangladesh from 12 different districts used Cannabis sativa to treat cited ailments like sleep-associated problems (n=5), neuropsychiatric and CNS problems (n=5), and infections and respiratory problems (n=5) followed by rheumatism, gastrointestinal, gynecological (n=4 each), cancer, sexual, and other ailments including hypertension, headache, itch, increases bile secretion, abortifacient, dandruff, fever, and urinary problems (n=1 each). There are a total of 15 formulations identified from the 11 out of 18 ethnomedicinal plant survey reports. The leaf was the main plant part used (53.8%), followed by root (23%), seed (7.7%) and flower, inflorescence, resin, and all parts 3.8% respectively. Conclusions Sales and cultivation of Cannabis are illegal at present in Bangladesh, but the use of Cannabis sativa as a natural phytomedicine has been practiced traditionally by folk medicine practitioners of Bangladesh for many years and validated through relevant pharmacological justification. Although Cannabis sativa possesses ethnomedicinal properties in the folk medicine of Bangladesh, it is, furthermore, needed to conduct biological research to consolidate pharmacological justification about the prospects and challenges of Cannabis and cannabinoids’ use in Bangladesh as safer biomedicine in the future.


Background
Medicinal plants are useful for healing properties since the ancient world and essential resources for developing biomedical drugs (Šantić et al., 2017(Šantić et al., , Souza et al., 2018. Ethnomedicine or traditional medicine knowledge usually refers to the medication of any particular culture that examines local ideas and behaviors of how to treat illness and how to stay healthy (Quinlan 2011). In General, ethnomedicinal knowledge is practiced and passed verbally from one generation to the members of the family of the following generation, and traditional medicine practices by utilizing medicinal plants are now being declined because of modernization and destruction of the medicinal plants, reduction of the interest in the younger generation, and switching to other jobs, but such knowledge of traditional medicine has been a way towards the invention of the many new medicines (Faruque et al. 2018, Singh et al. 2020. Bangladesh, officially the People's Republic of Bangladesh, is known as a country of cultural, ethnic, and language diversities. To date, this country has 7 divisions, 64 districts, 492 sub-districts, and 87,310 villages. The country possesses enormous resources of medicinal plants and traditional phytomedicine is still practiced throughout the country. Folk medicine practitioners (FMPs) in Bangladesh are commonly known as Kabiraj in the mainstream community and there are kabirajes in almost every village in Bangladesh. Kabirajes are important sources of ethnomedicinal knowledge which they have inherited from their ancestors (Rashid 2017). They enjoy considerable trust and support from their patients thanks to their holistic approach to treatment (Biswas et al. 2011). Kabirajes rely mainly on medicinal plants, dispensing medications for several health disorders and diseases including psychosis, cardiovascular disorders, eye infections, malaria, leucorrhea, leprosy, helminthic infections, urinary tract infections, sexually transmitted diseases, snakebite treatment, diabetes, gastrointestinal disorders, tumor, and cancer , Hasan et al. 2012, Hossan et al. 2010, Rahmatullah et al. 2010a, 2010b, 2010c, 2010h, 2012, 2012a. Each Kabiraj normally keeps his or her knowledge of medicinal plants within the family and passes this knowledge through from generation to generation. Over time, this knowledge becomes unique to the Kabiraj and his successors (Jahan et al. 2011).
Cannabis sativa is perhaps the most famous plant ever discovered by humans and the plant has a rich history with complex metabolic biology and fascinating physiology (Zwenger 2014). Cannabis sativa (hereafter referred to as "Cannabis") is an angiosperm belonging to the Cannabaceae family. For more than 5000 years, Cannabis sativa, also known as Marijuana, has been cultivated for fibers and source for seed oil (Lash 2010, Leizer et al. 2000 and for medicinal (Clarke andMerlin 2013, Zuardi 2006) and recreational use (Small 2017) around the world (Burstein 1997, Cota et al. 2003. In Arabic-Islamic medicine, Cannabis sativa extract has been used for its multiple curative properties such as diuretic, anti-emetic, anti-epileptic, anti-inflammatory, anti-parasitic, antipyretic, anti-bacteria, anti-tumor, vernucide and vermifuge, dermatic, carminative, and painkilling properties; the most used part was seeds; and the common methods of preparation were seeds' oil and juice from the leaves and green seeds' oil (Lozano 2001). Regardless, the Cannabis leaves alone have the potential to treat quite 25 different types of diseases (Kala et al. 2004), and other parts of the plant including the seeds, flowers, and roots are also being used.
Cannabis sativa is a wonder plant with over 500 chemical entities (Radwan et al. 2009) including over 100 phytocannabinoids and 120 terpenes (Calvi et al. 2018), of which less than 30 biosyntheses have been characterized (Booth and Bohlmann 2019). Phytocannabinoids are divided into 10 subclasses, i.e., cannabigerol, cannabichromene, cannabidiol, (−)-trans-Δ 9 -tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabitriol, and miscellaneous (Brenneisen 2007). There has been also a new phytocannabinoid identified which is called Δ9-tetrahydrocannabiphorol (Δ9-THCP) (Citti et al. 2019). Recently, the molecular pharmacology of the seven most phytocannabinoids (namely Δ9tetrahydrocannabinol, Δ9-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene) was investigated thoroughly (Turner et al. 2017), and 14 cannabinoids, 47 terpenoids, 3 sterols, and 7 flavonoids have been profiled in Cannabis flowers, leaves, stem barks, and roots for medicinal purposes (Jin et al. 2020). Moreover, the medicinal effects of Cannabis sativa are exploited within the treatment of epilepsy, pain, anxiety, depression, sleep disorders, nausea related to cancer treatment, and psychotic conditions, and it has antiglaucoma, antiemetic, antiobesity, and anticancer properties (Andre et al. 2016, Barrales-Cureño et al. 2020, Corroon and Phillips 2018. In addition, the government of Canada recognizes Cannabis sativa as an effective treatment for over two dozen conditions (Health Canada 2018). It is noteworthy that the scientific interest in Cannabis sativa was renewed in the early 1990s with the outline of cannabinoid receptors and therefore the identification of an endogenous cannabinoid system in the nervous system of humans (Zuardi 2006) wherein the pharmacological mechanisms of Cannabis metabolites would guide advances in therapies and changes in public health approaches (Russo and Marcu 2017).

History of Cannabis sativa cultivation in Bangladesh: usage and law
Cannabis has a long history of production and uses in Bangladesh. The British Empire began producing revenues from the production and trade of Cannabis goods in its South Asian territories in the early nineteenth century. Naogaon, a district of Bangladesh (formerly known as Eastern Bengal), was the single largest cultivation zone of Cannabis in colonial South Asia. The "Naogaon Ganja Cultivators' Cooperative Society limited" which was registered in 1917, was arguably the most successful cooperative in colonial India. The cooperative society obtained sole monopoly award from the British government and allowed it to control all sales of Cannabis (Chattopadhyaya 2018 , 1929-30, 1930). During the British colonialism period of the East India Company, Cannabis was marketed in Asia in a variety of formulations using flower and resin with low psychotropic content (named Bhang) and high psychoactive content (named Ganja or Charas) (Bonini et al. 2018). During the mid-twentieth century, many of the novels of a popular Bengali novelist Sarat Chandra Chattopadhyay reveal that smoking Ganja among the elderly people was common and socially accepted (Mahmud 2008). The use of ganja and its consumption for spiritual purposes has been practiced and tolerated in Bangladesh society for thousands of years (Haque 1993). The Muslims, particularly the Sufis of Bangladesh, have a tradition of using ganja for their spiritual purposes (Malek 1999). A leading English daily in Bangladesh reported on a 3-day traditional Ganja festival in 2004 and they published the following: "Thousands of marijuana or ganja lovers seeking spiritual ecstasy from across the country as well as from India, Nepal, Bhutan, Myanmar and Pakistan have started pouring in the 2,375 year-old Mahastangarh to celebrate a three-day ganja festival beginning today. The annual extravaganza, a crowd-puller, is held every last Thursday of the Bangla month of Boishakh and draws both male and female pot connoisseurs with plaited hair" (Bilu 2004; archive.thedailystar.net/2004/05/13/d4 0513011111.htm).
In 1971, marijuana became popular as a "natural drug" among the young generation due to the mental trauma of the historic War of Liberation and to avoid post-war suicidal tendencies among the glorious fighters. The renowned musician and author Maqsoodul Haque from the book of History of Bangladesh Rock, the legacy of Azam Khan stated the following: They lived, trained and fought for independence in villages where Marijuana was to a large degree socially acceptable. Its contribution to our Liberation War therefore must be acknowledged, because I personally know of at least a dozen past Mukti Bahini guerrillas who went into battle 'stoned out of their mind' to beat back fear and pain. (Haque 2020) The cultivation and sale of Cannabis is now illegal in Bangladesh; however, as per schedule I of the Narcotics Control Act, 1990, marijuana is a B-Class narcotics and section 9 of the Act has given permission to manufacture, process, import, export, supply, purchase, and sell narcotics for any approved medicine or for undertaking any scientific research which is being done under proper license, being used with the proper permit, and being carried or transported with proper pass (Joy 2017; www. thedailystar.net/law-our-rights/your-advocate-1419271) In this review, we aimed to document ethnomedicinal usage of Cannabis sativa by the FMPs of Bangladesh, retrieved from published ethnomedicinal plants' survey reports. We also reviewed the relevant scientific literature to consolidate the ethnomedicinal efficacy of Cannabis sativa in Bangladesh.

Methods and materials
The literature search for the ongoing study was conducted several times from August 2013 to March 2020 and updated on 3 December 2020 using the following multiple search terms through electronic sources of scientific databases like PubMed, Scopus, Science Direct, and Google Scholar: "ethnomedicinal Cannabis sativa and Bangladesh"; "Bangladesh cannabaceae and ethnomedicinal survey"; "ganja, bhang and folk medicine Bangladesh"; "tetrahydrocannabinol (THC), cannabinoid, and therapeutic, clinical trial"; "cannabis and pharmacological/biological"; etc.
Cannabis sativa together with other medicinal plants used as folk medicine has been documented randomly by Bangladeshi researchers from diverse affiliations through ethnomedicinal plant survey methods. Later, the study data have been published in English language by the authors in manuscript form in several journals. We identified these articles and retrieved information on the ethnomedicinal uses of Cannabis sativa reported by FMPs of Bangladesh.

Data analysis Plant part value (PPV)
The percentage of utilized plant parts (root, seed, leaves, flower, fruit, etc.) is calculated according to Gomez-Beloz (2002) as follows: Here, RU is the total number of uses reported of all parts of the plant and RU (plant part) is the sum of uses reported per part of the plant.

Ailments treated by the folk medicine practitioners (FMPs) in Bangladesh
It has been found that Bangladeshi FMPs from 12 different districts used Cannabis sativa to treat various ailments wherein the maximum number of cited ailment is sleep-associated problems (n=5), neuropsychiatric and CNS problems (n=5), and infections and respiratory problems (n=5) followed by rheumatism, gastrointestinal, gynecological (n=4 each), cancer, sexual, and other ailments (n=1 each) (see Table 1). Figure 1 shows the name of 12 districts of Bangladesh (Bagerhat, Gazipur, Jessore, Magura, Naogaon, Narayanganj, Natore, Netrakona, Rajshahi, Rangamati, Tangail and Thakurgaon) from where the ethnomedicinal plants' information was surveyed.
To the extent of our knowledge, there would be over 1000 ethnomedicinal plants' survey reports on Bangladesh published. For this review study, over 200 ethnomedicinal plants survey articles were reviewed wherein 18 survey articles have mentioned Cannabis sativa. A total of 15 formulations have been identified from the 11 articles where the rest of the studied articles did not mention any mode of preparation.
The authors of the identified articles conducted the ethnobotanical field survey using open-ended and semistructured questionnaire method. It is worth noting that there is at least one folk medicine practitioner in almost every village of Bangladesh. Most of the interviewed practitioners detailed in the identified articles are male reported to the use of Cannabis plant ).

Plant parts used and mode of preparation
Cannabis sativa leaf is the most frequently used plant part (53.8%) followed by root (23%), seed (7.7%), flower, inflorescence, resin, and all parts 3.8% respectively. FMPs generally follow simple preparation methods instead of a procedure of complex formulations. An oilbased preparation of Cannabis leaf is used to treat schizophrenia, and in severe conditions, leaves are used to make a vapor that is inhaled by the patient . Leaf juice is taken orally for treating bloating, cough, and mucus ), and leaf is also used to remove dandruff (Sultana and Rahman 2017). Macerated roots of Cannabis sativa and leaves of Chromolaena odorata are combined and taken for fever ). One teaspoon powder of dry, crushed Cannabis leaf is added to water and taken once a day orally as a CNS depressant and to treat arthritis pain (Mawla et al. 2012). Root is made into a paste with 25 black pepper and given twice daily to treat insanity, tetanus, pain of dysmenorrhea, menorrhagia, and phthisis; seed oil is useful in rheumatism, cancer chemotherapy, and cancer pain (Siddique et al. 2006). The smoke of dried pistillate of flowering tops of Cannabis plant is passed through the rectum for relief from strangulated hernia and griping pains of dysentery (Kadir et al. 2013) (see Table 2).

Discussion
We conducted an extensive study on combining detailed information on the traditional use of Cannabis sativa by folk medicine practitioners in Bangladesh. We corroborated ethnomedicinal usage of Cannabis sativa by pharmacological data. Our result indicates that different parts of the Cannabis plant were used by several folk medicine practitioners in Bangladesh to improve sleep quality, relief from pain, treating diseases, and psychological conditions, including gynecological diseases, sexual problems, gastrointestinal problems, various types of cancers, asthma, and respiratory problems, etc. (see Tables 1 and 2). Such a diverse set of cures and/or treatments have also been used by folk medicine practitioners and professionals around the world (Alsherbiny and Li 2018). One of the most common use of Cannabis found by our current study is to reduce or relieve from pain (Kadir et al. 2013, Mawla et al. 2012, Siddique et al. 2006, Sultana and Rahman 2017. It is worth mentioning that in the USA, the National Academies of Sciences, Engineering, and Medicine has supported the use of Cannabis in the treatment of chronic pain in adults through their analysis of the current scientific evidence (Romero-Sandoval et al. 2018), and a team of researchers also (Xiaoxue et al. 2019) found strong evidence that Cannabis with moderate high levels of THC can significantly alleviate pain. Cannabinoids may be useful in treating rheumatoid arthritis due to their antiinflammatory and immunomodulatory activity (Lowin et al. 2019, Sarzi-Puttini et al. 2019). Cannabis and cannabinoids have also potentials which showed promising results to alleviate pain related to rheumatic diseases (Gonen andAmital 2020, Haleem andWright 2020). In the century between 1842 and 1942, Cannabis was part of Western pharmacopeias preferred to other preparations by physicians in migraine treatment (Russo 2001). It was also used to treat headache/migraine in Bangladesh (Sultana and Rahman 2017) by folk medicine practitioners. A cannabis-derived medicine containing THC and CBD, Nabiximols, is approved in several countries for pain and muscle spasticity (Überall 2020).
Another interesting finding of the current study is that Cannabis most likely has the ability to improve sleep quality, decrease sleep disturbances, and decrease sleep onset latency (Kuhathasan et al. 2019, Nawaz et al. 2009). These findings align with a double-blind clinical trial, which showed success in treating chronic insomnia by using Zelira's proprietary cannabis formulation (ZTL-101) which was on target to launch in the Australian market by early Q3 2020 (Zelira Therapeutics 2020). Moreover, the use of cannabis to treat psychological conditions was also documented . A small randomized clinical trial reported clinical improvement in patients with schizophrenia treated with CBD (Iseger and Bossong 2015), and nine ongoing clinical trials have registered which focused on the effects of CBD on psychotic disorders (Batalla et al. 2019).
Bloating, cough, mucus. Leaf Leaf juice is taken orally for all three ailments.

Rahmatullah et al. 2009
Wound infections of cattle Leaf Not given Rashid et al. 2010 CNS depressant, gout, arthritic pain Leaf One teaspoon powder obtained from crushed and dried leaf is added to water and taken once orally.

Leaf
Paste from leaves which has been heated Walid et al. 2013 Schizophrenia like psychotic problems Leaf (a) Leaves are used to make oil then massage on the scalp until cured.
(b) If a patient is in severe condition, then the leaves are used to make vapor which is inhaled through the nose. Leaf, resin (a) Leaves make a good snuff for deterging the brain; juice removes dandruff (b) The resin called Charas is used to prevent and cure headache and asthma.

Sultana and Rahman 2017
Soporific, abortifacient Leaf, Not given Kona and Shakil et al. Journal of Cannabis Research (2021) 3:8 inhibit the capacity for male fertility (Payne et al. 2019). Despite this, Cannabis has been reported to be used as traditional aphrodisiac in Bangladesh (Nawaz et al. 2009, India, and the USA (Ross 2007). Cannabis was also used for traditional curative properties for asthma and respiratory problems in Bangladesh (Sultana and Rahman 2017), Cameroon (Noumi 2010), and South Africa (Ross 2007). Traditionally, Cannabis was also used to treat tuberculosis both in Bangladesh (Siddique et al. 2006) and South Africa (Lawal et al. 2014) as it exhibited antibacterial, antimicrobial properties (Appendino et al. 2008, Karas et al. 2020, Pellegrini et al. 2020. The contribution of cannabinoids in the treatment and management of gastrointestinal symptoms like nausea, vomiting, and visceral pain was found to be useful (Malik et al. 2015). The experimental data and robust preclinical evidence represent Cannabis and its compounds as a promising therapeutic in the treatment of intestinal inflammation and gastric mucosal lesions (Gyires and Zádori, 2016;Kienzl et al., 2020).
Cannabis was also mentioned for urination problems by FMPs of Bangladesh (Rahmatullah et al. 2010g, Walid et al. 2013). The 2004 clinical study discovered that Cannabis is effective which decreased urinary urgency, frequency, and urination at night in patients with advanced multiple sclerosis (Brady et al. 2004). Recent clinical trial studies showed the potentiality of cannabis medicine in improving lower urinary tract dysfunctions such as overactive bladder, interstitial cystitis/bladder pain syndrome, detrusor hyperreflexia, and urinary incontinence (Maniscalco et al. 2018, Nedumaran et al. 2017. Furthermore, Cannabis plant was also used by FMPs of Bangladesh for the treatment of various types of cancers (Mollik et al., 2010. Hence, cannabinoids have great promising therapeutic potential for the treatment of various cancers (Kovalchuk and Kovalchuk 2020); in particular, CBD has reported vigorous antiproliferative and pro-apoptotic effects on a wide variety of cancer types both in cultured cancer cell lines and in mouse tumor models. (Seltzer et al. 2020). Furthermore, traditional medicine practitioners in Zimbabwe used Cannabis sativa in cancer mainly for its analgesic, antinausea, and antiemetic properties (Matowa et al. 2020).
The endocannabinoid system and cannabinoids have started to get more and more considerable interests for therapeutic claims (Ryan et al. 2009) which could be observed by varieties of biological activities (Marcu 2016). Cannabis and cannabinoids can play the role of antinociceptive, anti-inflammatory, immunosuppressant antiemetogenic activity, and anticonvulsant activity (Mensah and Adu-Gyamfi 2019). Cannabidiol (CBD) has been identified as therapeutic in human laboratory studies and clinical trials for epilepsy, anxiety, pain/inflammation, schizophrenia, various substance use disorders, posttraumatic stress disorder, and others (Sholler et al. 2020). Furthermore, the usage of Cannabis for therapeutic purposes reported not to increase risk of harm to self or others (Walsh et al. 2017), and the UN Commission on Narcotic Drugs already removed Cannabis and Cannabis resin from a category of the world's most dangerous substances (CND 2020; news.un.org/en/story/2020/12/1079132). Already, 33 states in the USA and several countries in the world have been using Cannabis for specific medical conditions (Sarma et al. 2020). In June 2018, the US Food and Drug Administration (FDA) approved the first cannabis-derived medicine, Epidiolex® (cannabidiol, CBD), for the treatment of seizure disorders (Abu-Sawwa et al. 2020). However, Cannabis has been considered a narcotic drug, and its medicinal use ignored since the beginning of the twentieth century. It was the only recent decade that researchers started to conduct and follow up on the safe therapeutic potential of Cannabis sativa. It is worth mentioning that a search of the relevant scientific literatures provide support for the traditional usage of Cannabis sativa practiced by Bangladeshi folk medicine practitioners, thanks to the contribution of the cannabinoids to the unique biological properties.

Conclusions
Cannabis sativa is a plant of phytochemical factories. The plant has been used for thousands of years around the world for its apparent biological activity and has not been reported being more toxic than several medicines in current clinical practice. Although illegal, in Bangladesh, folk medicine practitioners use Cannabis extensively to treat a large kind of ailments such as sleep problems (insomnia, induce sleep, soporific); arthritis and pain (gout, rheumatism, cancer, and arthritic pain); gynecological disorders (dysmenorrhea, menorrhagia, expedite delivery); sexual problems (erectile dysfunction, sex stimulation, low libido, pleasant sensation); gastrointestinal problems (diarrhea, dyspepsia, strangulated hernia, poor digestion, dysentery); neuropsychiatric and CNS (paralysis, psychosis, insanity); infections and respiratory problems (tetanus, wound, tuberculosis, cough, asthma); cancer; and other ailments including hypertension, headache, itch, increases bile secretion, abortifacient, dandruff, fever, and urinary problems.
Based on the literature review we performed, there is significant scientific evidence that provides support for the usage of Cannabis sativa as a traditional phytomedicine by folk medicine practitioners of Bangladesh. It is also a need to perform more biological evaluation towards a ray of hope establishing therapeutic guidelines of Cannabis and cannabinoids and to provide a strengthened pharmacological perspective about the prospects and challenges of Cannabis use in the future.