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Cannabis sativa L. - Hemp

The medicinal usage of a named plant species

Adrian D Middleton
University of Sheffield
Certificate in Plant Studies
The Medicinal Properties of Plants
Summer 1997

This essay was written in 1997, but time moves on and attitudes are changing. A comprehensive House of Lords report in 1998 ( q.v.) gives a much more extensive (~100 page) summary of the medical evidence than I can give here. This paper was updated in 2001 and trials have begun in the UK to investigate the benefits.

As time allows (!) I will try and update the web-links in the bibliography.

In February of this year the US National Institute of Health held a "Workshop on the Medicinal Utility of Marijuana" to gather data on the therapeutic use of the drug [1]. Aimed at presenting facts which may lead the legalisation of marijuana for medical use, this is the latest step in the long history of Cannabis sativa as a medicinal plant, a history which since the 1930s has involved as much confusion and politics as information and medicine.

The plant - Cannabis sativa L.

Cannabis sativa is in the Cannabaceae or Hop family. Historically, three species have been described - C. sativa, a tall loosely branched plant over 10 feet high; C. indica, a shorter pyramidal, densely branched plant, 3 to 4 feet high; and C. ruderalis, which is only 2 feet high and un-branched. They are now regarded as a single highly variable species - C. sativa [2].

It is a dioecious erect annual herb which flowers in temperate regions from June to October but all year round in the tropics. Its leaves are generally divided into 5-7 serrated leaflets (up to 11 but reducing to 3 in upper leaves), are hairy and often sticky with resin. Basal leaves are opposite, upper leaves alternate. [3]

C. sativa is thought to have originated in central Asia, possibly in the area of the Caucasus, northern India, and Iran, and to have been spread to the north-west and to the south-east because of its various properties which relate to differing climate in these areas.

It is grown in temperate regions such as Russia and Europe, primarily for fibre and oil, and the 1856 edition of the Encyclopaedia Britannica traces its progress through the etymology of its common names - see Table 1 [4]. The fibre is harvested mainly from the taller male plants while the oil is produced from the seed taken from the female plants which may be left to develop after the male plants have been harvested. The first pressing of the seeds produced a cooking oil while a second pressing, using heat, produces a brown industrial oil used in paints and varnishes. The residue is then used as cattle feed [5].

The variety grown in India and other hot regions (formerly the species C. indica) produces an inferior fibre, but its resin is high in a variety of chemicals which have intoxicating and medicinal properties.

Hemp is still cultivated for fibre, oil and animal feed as well as for use as a narcotic and a herbal remedy. The seed are also used as bird food, which leads to Hemp being an occasional introduced weed even in Derbyshire [6].

History of medicinal use

Hemp was cultivated in China by 4,000BC and Turkestan by 3,000BC [7]. The first medicinal use is recorded in the reign of the Chinese emperor Chen Nung (or Shennung [8]) in about 3,000BC (or 2,000BC) for malaria, constipation, rheumatic pain, absentmindedness, and female disorders. Its use as an analgesic in surgery is also noted in an early Chinese herbal [9].

Herodotus (in 500BC) described how the Scythian horsemen inhaled the smoke from burning hemp seeds, and the Greek physician Galen (200BC) reported the use of hemp in cakes to increase the enjoyment of dinner parties [10]. Galen also noted its use as a remedy.

In 1621, Robert Burton, an English clergyman suggested cannabis as a treatment for depression, and Hemp root appears in the New English Dispensatory of 1794 as a remedy for skin inflammation [11].

The modern history of cannabis as a medicine began in India in 1839 when W B O'Shaughnessy reported its effectiveness in treating rabies, rheumatism, epilepsy, and tetanus, and also as an analgesic, muscle relaxant and anticonvulsant [12]. He returned to England in 1842 and cannabis rapidly became a popular treatment for many disorders, and became widely available. A report in 1860 included painful menstruation and childbirth, asthma and chronic bronchitis as benefiting from cannabis, and as a sleep-inducing drug, compared it to opium: "Its effects are less intense, and the secretions are not so much suppressed by it. Digestion is not disturbed; the appetite rather increased ... it is certainly often preferable to opium ..." [13]. It was even said to have been prescribed to Queen Victoria for menstrual cramps.

The herbal preparation came in various forms. The resin, known as 'churrus' or 'charas', was supposedly collected by men in leather clothes rushing through the hemp fields - it would adhere to their clothes and be scraped off and kneaded into cakes. More careful collection by hand yielded a finer product called 'momeea' or 'waxen churrus' The 'gunjah' or 'ganja' described by O'Shaughnessy is the dried plant harvested after removing the churrus, while 'bhang', 'subjee' or 'sidhee' consists of the dried leaves. 'Hashish' consists of resin collected by rubbing the plant between carpets! [14] and its name is related in history to the 'Assassins', a fanatical Muslim sect.

As both a medicinal herb, and a source of fibre, Hemp soon spread around the world, acquiring a variety of names such as 'dagga' in South Africa [15] and 'marihuana' (or 'marijuana') in America.

The narcotic properties of cannabis were noted as a side effect, and were more generally described as euphoria or hilarity, perhaps because of the low doses being used medicinally. Drug abuse was a problem at this time, and cannabis was reported to have been used successfully to treat opium and chloral hydrate addiction [16].

The medicinal use of cannabis was still being described in the 1930s [17]. It was still in the US Pharmacopoeia and National Formulary until 1941 [18], and remained available on prescription in the UK until 1971 [19]. Its popularity had however begun to decline as early as 1890. As with many herbal preparations its quality was variable, injectable opiates were increasingly being used for pain relief, and new synthetic drugs such as aspirin were appearing on the market.

In America, the Marihuana Tax Act of 1937, which was meant to prevent abuse but still allow medicinal use, effectively made cannabis unavailable legally. Ultimately in 1970, the US placed cannabis in Schedule I of the Controlled Substances Act which defines it as having no medical use, a high potential for abuse, and that it cannot be used safely even under medical supervision.

In Britain, the 1971 Misuse of Drugs Act classified cannabis as a Class B controlled substance 'with no medicinal uses' [20].

Chemistry and mode of action

Analysis of the cannabis plant shows over 460 known compounds of which 60+ have a structure called a 'cannabinoid'. Delta-9-tetrahydrocannabinol or THC has been the main subject of study since it is both psychoactive and present in large quantities (1-5%) in the indica sub-species - see Figure 1 [21].

Other constituents include olivetol - the biochemical pre-cursor of the cannabinoids [22]; cannabinol (CBN); and cannabidiol (CBD) - a non-psychoactive cannabinoid [23].

These are present in varying quantities determined by variety, climate and culture of the plant. In sequence, olivetol is converted to CBD, then to THC which is finally broken down to CBN as the plant matures [24].

These compounds have different individual actions. CBD, though not psychoactive, has now been shown to have anticonvulsant and antiepileptic properties [25] and to be more effective that THC and CBN as an analgesic and antiinflammatory [26]. Pure THC is used as an antiemetic (see later), but its psychoactive effects can be severe and may lead to catalepsy (unconsciousness) and panic reactions [27]. CBN has a much lower activity on all counts.

The exact actions of these compounds is still unclear. Though initially thought to be related to changes in the concentration of compounds such as adrenaline and seratonine [28], receptor sites have since been identified which are specific to cannabinoids and which inhibit the flow of calcium ions associated with the release of neurotransmitter compounds [29].

Identification of the cannabinoid receptors suggested that the body produces its own 'cannabis-like' compound. This has now been isolated from brain tissue and identified as 'anandamide' - described in a recent abstract as 'a substance of inner bliss' [30].

THC related compounds have now been produced synthetically and marketed as Synhexyl, Nabilone and Levonatradol, while synthetic THC is marketed as Dronabinol and Marinol [31], which comprises pure THC in sesame seed oil [32]. Though the plant remains a Schedule I drug in the US, synthetic THC was moved to Schedule II in 1985 and can be prescribed.

As with many herbal remedies, it is believed that the combination of chemicals contributes to and modifies the overall action. Research has demonstrated this with cannabis - pure THC induced catalepsy in mice which cannabis oil and mixtures of cannabinoids did not [33]; and CBD has been shown to reduce the panic and anxiety reactions associated with pure THC [34].

Recent evidence

Two of the major modern uses of cannabis arise from problems not encountered until this century - Cancer Chemotherapy and AIDS. In spite of legal problems in obtaining the drug, anecdotal evidence began to mount in the 1960s that cannabis could ease the problems of nausea and loss of appetite associated with cancer chemotherapy. A range of studies have confirmed this effect [35].

Approval was given in the USA in 1985 for the use of synthetic THC (Marinol) as a prescription treatment in such cases, but several studies have shown that the pure form of the compound has stronger psychoactive side effects, and is less easily controlled than smoked marijuana. In addition many patients found the oral THC pill difficult to take when feeling nauseous, while the inhaled drug had an immediate effect [36]. Again the combination of active compounds is thought to be important.

In 1991 a survey of oncologists [37] reported that 44% (of 1035 respondents) had recommended marijuana to their patients, while 54% favoured it being available on prescription.

Marinol has also been approved as an appetite stimulant in the treatment of AIDS Wasting Syndrome. As with chemotherapy, many patients prefer smoked marijuana (for the same reasons) and many use it albeit illegally. Worries have been raised about the effect on the lungs, but what little evidence there is comes from patients who also smoke tobacco and other illegal drugs [38].

Glaucoma is a third condition for which cannabis has recently been investigated. A reduction in intraocular pressure (IOP) due to cannabis was first reported in 1971 [39]. Several other studies followed but the psychoactive side effects have prevented its widespread use. A paper in 1981 [40] isolated a compound which lowered IOP in albino rabbits and showed that it was not a cannabinoid structure. Though glaucoma is often quoted as a potential use of cannabis, no further work seems to have been done. A researcher recently stated that "I have no idea how this drug works as a treatment for glaucoma" [41].

Other modern uses are based on properties which have been known for many years - e.g. the ability of cannabis to control pain, including migraine - but most evidence is still anecdotal because of the legal issues over its use, and is mainly available from sources aiming at its legalisation - hence they tend to overstate its benefits (as noted above for glaucoma).

Perhaps the most important such potential use is for Multiple Sclerosis (MS) and relates directly to O'Shaugnessy's use of cannabis as an anticonvulsant. MS involves a deterioration in the function of the nervous system, and a number of cases have been found where the use of cannabis helps at least with the symptoms of MS which include tremors, muscle spasms and loss of balance and bladder control [42]. These effects are now thought to relate to a non-psychoactive compound within cannabis - cannabidiol (CBD) [43].

The future

Attitudes to cannabis in the last 60 years have been influenced by politics and the fear of drug abuse as much as by scientific evidence. Though much research was done in the 1960s and 1970s, recent US administrations have blocked the supply of cannabis for research, and in December 1996 a senior official stated that marijuana has no medical value at all [44].

In 1988 after two years of hearings, Francis L Young, the Chief Administrative Law Judge with the US Drug Enforcement Administration (DEA) ruled that marijuana is "one of the safest therapeutically active substances known", and that it should rescheduled and made available on prescription [45]. The DEA rejected the ruling. Many researchers, users and doctors hope that the recent NIH workshop will lead to a change of policy.

Footnotes

[1] NIH workshop held on 19-20 February 1997 reported in Gwynne (1997).

[2] Grinspoon and Bakalar (1993).

[3] Duke (1984). and Snyder (1996).

[4] Encyclopaedia Britannica (1856).

[5] http://ifs.plants.ox.ac.uk/fao/tropfeed/data/r494.html .

[6] Clapham (1969).

[7] Grinspoon and Bakalar (1993).

[8] Mann (1992).

[9] Grinspoon and Bakalar (1993).

[10] Mann (1992).

[11] Burton (1621), etc. noted in Grinspoon L and Bakalar J B (1993).

[12] O'Shaughnessy (1839) noted in Encyclopaedia Britannica (1856), Wood & Bache (1843), and in Grinspoon and Bakalar (1993).

[13] M'Meens (1860) noted in Grinspoon and Bakalar (1993).

[14] Encyclopaedia Britannica (1856), and Grieve (1931).

[15] Field and Arndt (1980).

[16] Birch (1889) and Mattison (1891) noted in Grinspoon L and Bakalar J B (1993).

[17] Grieve M (1931).

[18] Grinspoon L and Bakalar J B (1993).

[19] Noted in House of Commons Early Day Motion 158 raised by Paul Flynn MP 7/11/1996 - http://foobar.co.uk/users/ukcia/politics/edm.html .

[20] Note on "UK Cannabis Laws" at http://foobar.co.uk/users/ukcia/law/index.html .

[21] From Snyder L A (1996).

[22] Formukong, Evans and Evans (1988b).

[23] Samara, Bialer and Mechoulam (1988).

[24] Grinspoon L and Bakalar J B (1993).

[25] Samara, Bialer and Mechoulam (1988).

[26] Formukung, Evans and Evans (1988b).

[27] Gieringer (1996).

[28] Mann J (1992).

[29] Mackie and Hille (1992).

[30] Onaivi, Chakrabarti and Chaudhuri (1996).

[31] Grinspoon L and Bakalar J B (1993) and Snyder L A (1996).

[32] Zeese (1997).

[33] Formukung, Evans and Evans (1988a).

[34] Zuardi (1982) quoted in Gieringer (1996).

[35] e.g. Sallan et al (1975) through to Vinciguerra et al (1988).

[36] Zeese (1997).

[37] Doblin and Kleiman (1991).

[38] Gieringer (1996).

[39] Hepler and Frank (1971).

[40] Deutsch et al (1981).

[41] Paul Kaufman (Univ. of Wisconsin) at the NIH workshop held on 19-20 February 1997 reported in Gwynne P (1997).

[42] Wills (1995) and others notes in http://www.foobar.co.uk/users/ukcia/medical/ms.html .

[43] Samara, Bialer and Mechoulam (1988).

[44] Barry R McCaffrey (Director of the Office of National Drug Control Policy) quoted in Gwynne (1997) and Zeese (1997).

[45] Grinspoon and Bakalar (1993) and others.

Bibliography

Birch E A (1889) "The use of Indian Hemp in the treatment of chronic Chloral and chronic Opium Poisoning". Lancet. 1, p625.

Burton R (1621). The Anatomy of Melancholy.

Clapham A R (1969). Flora of Derbyshire. Reprinted 1992 by Ashbourne Editions. Ashbourne.

Deutsch H M, Green K and Zalkow L H (1981)
"Isolation of ocular hypotensive agents from Cannabis sativa". J Clin Pharmacol. 21(8-9 Suppl), p479S-485S. (Aug 1981)

Doblin R and Kleiman M (1991).
"Marihuana as Anti-emetic Medicine: A survey of Oncologists Attitudes and Experiences". Journal of Clinical Oncology. 9, p1275-80.

Duke J A (1984). "Cannabis sativa" in Handbook of Energy Crops. Unpublished, but available on http://www.hort.purdue.edu/newcrop/duke_energy/Cannabis_sativa .

Encyclopaedia Britannica (1856).
"Hemp" in Encyclopaedia Britannica Eight Edition Volume XI, 1856, reprinted on http://www.botanical.com/botanical/mgmh/h/hemp22a.html .

Field B I and Arndt R R (1980)
"Cannabinoid compounds in South African Cannabis sativa L." J Pharm Pharmacology. 32(1), p21-24. (Jan 1980)

Formukung E A, Evans A T and Evans F J (1988a).
"Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L." Journal of Pharmacy and Pharmacology. 40(2), p132-4. (Feb 1988)

Formukung E A, Evans A T and Evans F J (1988b).
"Analgesic and antiinflammatory activity of constituents of Cannabis sativa L." Inflammation. 12(4), p361-371. (Aug 1988)

Gieringer D H (1996) "Review of Human Studies on Medical Use of Marijuana" at http://www.natlnorml.org/medical/medmj.studies.shtm .

Grieve M (1931). A Modern Herbal. Penguin. (http://www.botanical.com/botanical/mgmh/mgmh.html)

Grinspoon L and Bakalar J B (1993).
"The History of Cannabis" in Marihuana: The Forbidden Medicine. Yale Univ Press. New Haven. (http://www.lindesmith.org/mmjgrins.html)

Gwynne P (1997). "Medical Marijuana Debate Moving Toward Closure". The Scientist. 11(7). p1-6. (31 March 1997) (http://www.the-scientist.library.upenn.edu/yr1997/mar/
gwynne_p1_970331.html)

Hepler R S and Frank I R (1971)
"Marihuana smoking and intraocular pressure". JAMA. 217, p1392.

Mackie K and Hille B (1992)
"Cannabinoids inhibit N-type calcium channels in neuroblastoma-gioma cells". Proc Natl Acad Sci USA. 89(9), p3825-9. (May 1992)

Mann J (1992). Murder, Magic and Medicine. OUP. Oxford.

Mattison J B (1891) "Cannabis indica as an Anodyne and Hypnotic". St Louis Medical Surgical Journal. 61, p266.

M'Meens R R (1860) "Report of the Committee on Cannabis indica" in Transactions, 15th Annual Meeting of the Ohio State Medical Society, Columbus, 1860.

Onaivi E S, Chakrabarti A and Chaudhuri G (1996)
"Cannabinoid receptor genes". Prog Neurobiol. 48(4-5), p275-305. (Mar 1996)

O'Shaughnessy W B (1839)
"On the preparations of Indian Hemp, or Gunjah (Cannabis indica): The effects on the Animal System in Health, and their utility in the treatment of Tetanus and other convulsive diseases". Transactions of the Medical and Physical Society of Bengal (1838-1840). p421-461.

Sallan S, Zinberg N and Frei E (1975).
"Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy". New England Journal of Medicine. 293(16), p795-7.

Samara E, Bialer M and Mechoulam R (1988)
"Pharmacokinetics of cannabidiol in dogs". Drug Metab Dispos. 16(3), p469-472. (May 1988)

Snyder L A (1996). "Description and Natural History of Hemp" and "Pharmacology of Tetrahydrocannabinol" in 'Cyberbotanica' at http://biotech.chem.indianan.edu/botany/hemphist.html and .../the.html

Vinciguerre V, Moore T and Brennan E (1988)
"Inhalation marijuana as an antiemetic for cancer chemotherapy". New York State Journal of Medicine. 88, p525-7. (Oct 1988)

Wills S (1995) "The use of cannabis in multiple sclerosis". The Pharmaceutical Journal. 255 p237-8.

Wood G B and Bache F (1843)
"Cannabis sativa - Hemp" in The Dispensatory of the United States of America (5th ed.). Philadelphia. (extract available at http://www.lycaeum.org/~sputnik/Ludlow/Texts/dispensa.html).

Zeese Z B (1997) "Research Findings on the Medicinal Properties of Marijuana" - January 1997 - on http://www.lindesmith.org/mmjcsdp.html .

Zuardi A W et al (1982) "Action of cannabidiol on the anxiety and other effects produced by delta-9-THC in normal subjects". Psychopharmacology. 76, p245-250.

As will be noted above, many of these references have been accessed via the Internet World-Wide-Web (WWW). Where possible they have been filtered for reliability, mainly based on the source (e.g. University departments) though some relate to web pages set up by pressure groups and interested individuals.

Many of the scientific references arise from other articles or from searches of the Medline abstract database via the US National Institute of Health web site (http://www.ncbi.nlm.nih.gov/PubMed). In general the details given here are taken from abstracts on Medline - the full articles have not been consulted.