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It is probable that plants of the genus Sceletium (Mesembryanthemaceae) have been used as masticatories and for the relief of thirst and hunger, to combat fatigue, as medicines, and for social and spiritual purposes by San hunter-gatherers (historically referred to as Bushmen) and Khoi pastoralists (historically referred to as Hottentots) for millennia before the earliest written reports of the uses of these plants by European explorers and settlers. The oral-tradition knowledge of the uses of Sceletium by indigenous peoples has largely been eroded over the last three centuries due to conflicts with settlers, genocidal raids against the San, loss of land, the ravages of introduced diseases, and acculturation. Wild resources of Sceletium have also been severely diminished by over-harvesting, poor veld-management, and possibly also by plant diseases. Sceletium was reviewed almost a decade ago and new results have emerged substantiating some of the traditional uses of one of South Africa's most coveted botanical assets, and suggesting dietary supplement, phytomedicine and new drug applications. This review aims to collate the fragmented information on past and present uses, the alkaloid chemistry and pharmacological evidence generated on Sceletium.
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Journal of Ethnopharmacology 119 (2008) 653–663
Contents lists available at ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm
Review
Sceletium—A review update
N. Gerickea, A.M. Viljoenb,
aP.O. Box 937, Sun Valley 7985, South Africa
bDepartment of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria 0001, South Africa
article info
Article history:
Received 5 May 2008
Received in revised form 16 July 2008
Accepted 21 July 2008
Available online 8 August 2008
Keywords:
Alkaloid
Ethnobotany
Mesembryanthemaceae
Sceletium
abstract
It is probable that plants of the genus Sceletium (Mesembryanthemaceae) have been used as masticato-
ries and for the relief of thirst and hunger, to combat fatigue, as medicines, and for social and spiritual
purposes by San hunter-gatherers (historically referred to as Bushmen) and Khoi pastoralists (historically
referred to as Hottentots) for millennia before the earliest written reports of the uses of these plants
by European explorers and settlers. The oral-tradition knowledge of the uses of Sceletium by indigenous
peoples has largely been eroded over the last three centuries due to conflicts with settlers, genocidal
raids against the San, loss of land, the ravages of introduced diseases, and acculturation. Wild resources
of Sceletium have also been severely diminished by over-harvesting, poor veld-management, and possi-
bly also by plant diseases. Sceletium was reviewed almost a decade ago and new results have emerged
substantiating some of the traditional uses of one of South Africa’s most coveted botanical assets,and sug-
gesting dietary supplement, phytomedicine and new drug applications. This review aims to collate the
fragmented information on past and present uses, the alkaloid chemistry and pharmacological evidence
generated on Sceletium.
© 2008 Published by Elsevier Ireland Ltd.
Contents
1. Introduction ......................................................................................................................................... 654
2. Botanical aspects .................................................................................................................................... 654
3. Historical record .................................................................................................................................... 655
4. Recent ethnobotany................................................................................................................................ . 656
5. Alkaloid chemistry .................................................................................................................................. 657
6. Pharmacological activity ............................................................................................................................ 660
6.1. In vitro studies ............................................................................................................................... 660
6.2. In vivo studies ............................................................................................................................... 660
6.2.1. Historical ........................................................................................................................... 660
6.2.2. Safety .............................................................................................................................. 660
6.2.3. Efficacy ............................................................................................................................. 661
6.2.4. Anecdotal/clinical data ............................................................................................................ 661
6.2.5. Clinical case reports ............................................................................................................... 661
7. Concluding comments .............................................................................................................................. 662
Acknowledgments .................................................................................................................................. 662
References .......................................................................................................................................... 663
Corresponding author. Tel.: +27 12 3826360; fax: +27 12 3826243.
E-mail addresses: viljoenam@tut.ac.za,alvaroviljoen69@yahoo.com (A.M. Viljoen).
0378-8741/$ – see front matter © 2008 Published by Elsevier Ireland Ltd.
doi:10.1016/j.jep.2008.07.043
654 N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663
1. Introduction
Sceletium species are among the most commercially promising
South African plants, with potential applications of raw material,
extracts and isolated compounds spanning dietary supplement,
natural medicine, veterinary and pharmaceutical uses. More than
a decade has passed since the first ethnopharmacological review
of this genus by Smith et al. (1996). There have since been signifi-
cant advances in all aspects of Sceletium research, and an increasing
number of commercial Sceletium products have appeared in the
market place. Commercial Sceletium plantations have been estab-
lished to address the need for sustainable supplies of standardised
high quality raw material. The purpose of this review is to provide a
short historical overview together with a comprehensive summary
of past and recent developments in the chemistry, pharmacology,
veterinary and clinical applications of Sceletium, and to highlight
the lacunae in our present knowledge of this fascinating endemic
South African succulent genus.
2. Botanical aspects
The generic circumscription of Sceletium (Aizoaceae, subfam-
ily Mesembryanthemoideae) had been reconsidered by various
authors since the genus had been established in 1925 by N.E.
Brown. This group of plants is characterised by the skeletonised
leaf venation pattern visible in dried leaves (Fig. 1). In 1986,
Bittrich argued for a broader circumscription of Phyllobolus which
included Sceletium as one of five subgenera. Since Gerbaulet was
unable to find a synapomorphy (a unique derived character) for
Bittrich’s broad concept of Phyllobolus, she reinstated Sceletium
as a genus (Gerbaulet, 1996). Using molecular techniques in
combination with morphological characters, Klak et al. (2007) pro-
posed a much expanded generic concept, whereby a single genus,
Mesembryanthemum (including Sceletium), is recognized in the
Mesembryanthemoideae. (For the purpose of this review Sceletium
Fig. 1. Sceletium leaves showing the distinctive idiobasts on the leaf surface and the
characteristic skeletonised appearance of the old leaves.
Fig. 2. Sceletium species are characterised by their decumbent habit, succulent
leaves and flowers ranging fromwhite, to light yellow or pink. (For interpretation of
the references to color in this figure legend, the readeris referred to the web version
of the article.)
tortuosum (L.) N.E. Br. (=Mesembryanthemum tortuosum L.) will be
used).
The genus name is derived from ‘sceletus’ meaning skeleton
which refers to the prominent lignified veins visible in the dry
and withered leaves (Fig. 1). Of the 22 species described by Brown
(1926), 8 were recognized in the revision of Gerbaulet (1996);
Sceletium crassicaule (Haw.) L. Bolus, Sceletium emarcidum (Thunb.)
L. Bolus ex H.J. Jacobson, Sceletium exalatum Gerbaulet, Sceletium
expansum (L.) L. Bolus, Sceletium rigidum, L. Bolus, Sceletium stric-
tum L. Bolus, Sceletium tortuosum and Sceletium varians (Haw.)
Gerbaulet. The species are distinguished on the basis of vegeta-
tive, flower, fruit and seed characteristics. In this revision several
species are reduced to synonymy including Sceletium joubertii L.
Bol., and Sceletium namaquense L. Bol. now considered to be part
of Sceletium tortuosum.Sceletium exhibits a climbing or decum-
bent habit and have characteristic succulent leaves with “bladder
cells” or idioblasts. The flowers range from white, yellow to pale
pink (Fig. 2). The fruit capsule contains numerous kidney-shaped
seeds which are brown to black in color. The genus is distributed in
the south-western parts of South Africa and has an affinity for arid
environments (Fig. 3). The vernacular names include kanna (Khoi)
and kougoed (Afrikaans), the latter referring to the use of the plant
material by chewing.
Fig. 3. Geographical distribution of Sceletium in South Africa (redrawn from Smith
et al., 1998a,b).
N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663 655
3. Historical record
The earliest unambiguous illustration of a Sceletium plant is a
painting of the plant in the journal of Cape of Good Hope Gov-
ernor Simon van der Stel’s expedition to Namaqualand in 1685
(Waterhouse et al., 1979; Smith et al., 1996; Scott and Hewett,
2008). There are two surviving copies of the painting, originally
made by the apothecary Hendrik Claudius who accompanied this
expedition, one in a collection at the library of Trinity College,
Dublin (Waterhouseet al., 1979) and one in a volume of water colors
known as the Codex Witsenii at the South African Museum in Cape
Town(Wijnands et al., 1996). Both paintings showa flower typical of
Sceletium as well as the characteristic skeletonised old lower leaves
from which the genus name Sceletium is derived (Jackson, 1990).
The species of Sceletium illustrated is not identifiable, but may
represent Sceletium expansum (Scott and Hewett, 2008), Sceletium
tortuosum,orSceletium strictum (Fig. 4).
The information accompanying the illustration has been trans-
lated from the original Dutch (Waterhouse et al., 1979): “This plant
is found with the Namaquas and then only on some of their moun-
tains. It is gathered in October and is called Canna. It is held by them
and surrounding tribes in as great esteem as the betel or areca with
the Indians. They chew its stem as well as its roots, mostly all day,
and become intoxicated by it, so that on account of this effect and
its fragrance and hearty taste one can judge and expect some profit
from its cultivation.”
The Namaqua name for Sceletium, recorded as Canna in Simon
van der Stel’s journal, was later spelled as kanna by other writ-
Fig. 4. Painting of a Sceletium species from Simon van der Stel’s Journal of 1685.
ers (Smith, 1966). Some uncertainty has been caused by the
occasional use of the same folk name, kanna, for plants of the
genus Salsola, which are more commonly known as ganna (Smith,
196 6). However there is no historical or extant evidence to
suggest that Salsola species have masticatory, hunger- and thirst-
relieving, mood-enhancing or other properties valued in Sceletium.
In 1662, the Namaquas gave kanna and sheep to the Dutch in
exchange for gifts, and the Commander of the Cape of Good Hope,
Jan van Riebeek, regarded kanna as similar to ginseng (Smith,
196 6).
Kolben noted in 1738 that kanna was the “greatest Chearer of
the Spirits, and the noblest Restorative in the World” (Smith et al.,
1996). In 1924, Lewin noted that under the name kanna or channa,
Kolben was referring to a plant whose root was used by the Hot-
tentots as a means of enjoyment, which they “chewed, kept in their
mouth for some time, thus becoming excited and intoxicated”, and
the name channa designates certain species of Sceletium including
Sceletium expansum and Sceletium tortuosum (Lewin, 1998). Both
these species were illustrated in the 18th century (Emboden, 1979)
(Fig. 5a and b).
Carl Peter Thunberg, the Swedish botanist and physician who
had been a student of Linneaus, made two journeys to the Eastern
Cape between 1772 and 1774 and reported that valuable narcotic
plants were found in the vicinity of the present-day town of Oudt-
shoorn in the Little Karoo, in the territory known as ‘Cannaland’,
and formerly occupied by the Attaqua Khoikhoi (Gordon, 1996).
This area of South Africa is still known as Cannaland at the present
time. According to Thunberg (Forbes, 1986): “Kon, was a name given
by the Hottentots to a shrub which grew here (Mesembryanthe-
mum emarcidum) [now Sceletium emarcidum] and was famous all
over the country. The Hottentots came far and near to fetch this
shrub with the root, stalk and leaves which they stamp together,
and afterwards twist them up like pig-tail tobacco; after which they
let the mass ferment, and keep it by them for chewing, especially
when they are thirsty. If chewed immediately after fermentation,
it intoxicates. The word kon is said to signify a quid; the colonists
call it canna root. It is found in the driest fields only, and is gathered
chiefly by the Hottentots, who live near this spot. These afterwards
hawke it about, frequently to a great distance, and exchange it
for cattle and other commodities.” In this passage, Thunberg him-
self identifies the plant as Mesembryanthemum emarcidum,now
Sceletium emarcidum. Thunberg further reported that the San “first
chew canna (Mesembryanthemum), and afterwards smoke it”. The
notes to this passage by the editor identifies canna as “various
species of Sceletium, especially Sceletium tortuosum (Mesembryan-
themaceae), esteemed for their narcotic properties when chewed
or smoked” (Forbes, 1986). Thunberg reports on the use of Sceletium
by the Khoi for quenching thirst, after first having been allowed to
putrify.
It has been suggested that the Sceletium growing in the vicinity
of the former areas of Attaqua and Inqua settlement allowed for the
rise of powerful Khoi traders in Sceletium (Gordon, 1996). The Karoo
also featured as a centre of Sceletium trade in the mid-nineteenth
century when people of mixed Khoi and white ancestry traded in
Sceletium, which was used to treat insomnia in adults, diarrhoea in
children, and also chewed as a mild narcotic or intoxicant (Digby,
2005).
The Afrikaans vernacular name kougoed, derived from “kou”(to
chew) and “goed” (stuff) was first recorded for Sceletium tortuo-
sum in about 1830 (Smith, 1966). Kauwgoed, was reported to be
the leaves of a species of Sceletium (Laidler, 1928). Pappe included
Mesembryanthemum tortuosum [=Sceletium tortuosum] in his Florae
Capensis Medicae Prodromus. This book was intended as a com-
mentary accompanying a “choice collection of Cape medical drugs
sent by Messrs S.H. Scheuble & Co. to the Great London Exhibition of
656 N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663
Fig. 5. (a) Eighteenth century woodcut of Sceletium expansum and (b) Eighteenth century woodcut of Sceletium tortuosum.
1851.” (Gunn and Codd, 1981). “This native of the Karoo appears to
possess narcotic properties. The Hottentots, who know it as Kauw-
goed, are in the habit of chewing it and become intoxicated, while
the farmers use it in the form of a decoction or tincture, as a good
sedative” (Pappe, 1868).
According to Meiring, Sceletium tortuosum was reportedly
widely used for its soporific effect on young children, including
quieting them when suffering from “acidity”. One to two drops of
fresh juice from green plants was given to a child who would enjoy
a deep, quiet rest for a few hours (Meiring, 1898).
Hartwich and Zwicky (1914) conclude their scientific commu-
nication on Sceletium expansum and Sceletium tortuosum by stating
that the indigenous people undoubtedly used the plant more for
enjoyment than as a medicine. Although Sceletium is most com-
monly chewed, it is also used as a tea (Jacobsen, 1960; Smith et al.,
1996; Van Wyk and Wink, 2004), taken as a tincture (Pappe, 1868),
and occasionally used as a snuff or smoked.
The above-ground parts of both Sceletium expansum and
Sceletium tortuosum are used in Namaqualand to make kougoed
(Watt and Breyer-Brandwijk, 1962). Sceletium tortuosum has been
chewed for the relief of toothache and abdominal pains, and is used
by Nama people for the relief of pain and for the relief of hunger,
while Nama mothers have been reported to chew the roots and
spit the resulting saliva into a babies mouth (Watt and Breyer-
Brandwijk, 1962). San mothers are reported to have used Sceletium
anatomicum [=Sceletium emarcidum] in the same way (Rood, 1994).
Palmer reported that the juice of Sceletium strictum was used for
teething in babies, and that Sceletium anatomicum [=Sceletium emar-
cidum] had once been the most popular member of the genus
for the Khoi (Palmer, 1966). Rood includes the Afrikaans name
tandtrekbos” under the entry for Sceletium anatomicum [=Sceletium
emarcidum] translated as “tooth-pulling bush” and quotes a report
by Mr. P. van Breda, that if enough plant is eaten it can anaesthetize
the lower jaw so that teeth can be pulled painlessly. The juice of
the leaves of Sceletium anatomicum [=Sceletium emarcidum], mixed
with a little milk is given to babies as a sleeping remedy, while
chewing the leaves has a calming action, and is an excellent remedy
for stomach problems (Rood, 1994).
Herre noted there were storekeepers in Namaqualand buying
Sceletium from the locals for re-sale to others (Herre, 1971), and
this retail trade continues to this day in rural trading stores when
supplies are available.
4. Recent ethnobotany
Excerpts from a translated interview with a local shepherd
in Namaqualand, Mr. Lodewyk Mories, recorded on audiotape in
Afrikaans in May, 1995 (Mories, pers. comm. 1995), part of which
had first been reported in Smith et al. (1996):
Kougoed hides under other bushes. Occasionally it does grow
in the open, but in general it prefers to grow under a bush. It
has a small seed, so it blows to places where it is stopped, and
it lies there and grows.... The plant grows in winter, when the
rains come. In the summer when the growing is over, and the
leaves get yellowish and wilted, it is at its best. At the end of
the growing season when most of the leaves are dead, then it is
more powerful. It still work when its green, but it is very juicy,
and you will lose a lot through the juice that drains out. You
pick the kougoed, cut off the root, and crush it with a rock, put
it in a plastic bag, and tie it tightly. You can leave it in the sun
to get warm. It is not necessary to keep it in the shade, it gets
shade at night, and the sun doesn’t harm it. The plant is left to
sweat. After two to three days you mix it all together, and close
it up again for another five to six days. On the eighth day after
crushing you open it and spread out to dry in the sun as when
you dry raisins. You leave it out until it is dry. If you do not do the
whole process, the plant won’t have power.... Small plants are
not picked and are left for the following season. If you want to
make kougoed for immediate use you can make a fire, scrape a
hollow in the sand, put in [the freshly picked plant], cover with
hot sand and leave for an hour.
You use it when you feel like it.... You use it, then take it out
of your mouth, and use it again when you want to....Itisnot
a poison; there is no such thing as too much...... Iamusedto
using it, I use it when I feel like it.... I ate a lot of kougoed, but
now in my later years I am not so partial to it. Sometimes I eat it,
and sometimes I don’t eat it for days. Sometimes I stay a month
without it, but if I feel like it, then I will chew it.
[For use in infants] ...a long-tailed sheep is slaughtered, the
end portion of the tail is kept and scalded in hot water, and the
hair scraped off. The softest part of the fat of a sheep is at the
end of the tail. The tail is cut into fine pieces and fried together
with kougoed. About [indicated a piece about 6 cm long] of the
N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663 657
tail is used with a large pinch of kougoed [about a tablespoonful
indicated]. When cool the oil is filtered through a cloth to get rid
of the small pieces and sticks, and kept in a small bottle. ...You
use this for colic in babies, a teaspoon at a time given by mouth.
It remains liquid. Another way is to put about 14of a teaspoon of
kougoed into a small piece of linen cloth; if you put more, say 12a
teaspoon, the baby will sleep for hours—you mustn’t make it too
strong. A few drops of mothers’ milk is put in a spoon, and the
cloth containing kougoed is dipped in the milk and pressed until
the milk becomes brown in color. The brown liquid is given to
the baby. The baby won’t suck on the cloth because it is salty and
they don’t like the taste. If the child has winds or cramps, then it
will sleep because the discomfort is relieved. The stomach will
also work. If you don’t have milk you can use lukewarm water,
and squeeze a few drops into the baby’s mouth.
Kougoed can be used together with alcohol; some people use
them together, but you can also use it alone.... There was a
lot of kougoed in the old days, and you could sell it to the
shops. Then the people ran after the money. This was about
fifty years ago [about 1945], when I was about 16 or 17 years
old. Many people sold it. In Springbok [a town in Namaqua-
land] the shop-owners said that you must bring them kougoed.
There are still shops that sell it. .... The sheep are not the rea-
son there is so little left. I looked after sheep night and day for
many years, and walked behind them. They taste it here and
there, but it is not a main food. It is almost an accident that
they take it. Many people say the sheep destroyed it, but this is
not true.”
5. Alkaloid chemistry
The genus Sceletium, as for the family Amaryllidacae, pro-
duces alkaloids belonging to the crinane class of compounds.
Based on the alkaloid skeleton, Jeffs et al. (1982) categorises the
various Sceletium alkaloids into four structural groups: (1) the 3a-
aryl-cis-octahydroindole class (e.g. mesembrine), (2) the C-seco
mesembrine alkaloids (e.g. joubertiamine), (3) alkaloids contain-
ing a 2,3-disubstituted pyridine moiety and 2 nitrogen atoms (e.g.
Sceletium alkaloid A4) and (4) a ring C-seco Sceletium alkaloid
A4group (e.g. tortuosamine). The revision of Gerbaulet (1996)
recognizes 8 species of Sceletium of which Sceletium strictum,
Sceletium subvelutum (=Sceletium varians), Sceletium tortuosum,
Sceletium joubertii and Sceletium namaquense have been stud-
ied exhaustively for their alkaloid composition. The latter two
species are now considered synonyms of Sceletium tortuosum. Tak-
ing into consideration that the local utilization of Sceletium has
included a number of species, that chemotypic variation is pos-
sible within a species, and that there is continued debate around
the taxonomic nomenclature of the various taxa (and the Mesem-
bryanthemaceae in general), all compounds that haveb een isolated
from the genus Sceletium have been included, and presented in
Fig. 6.
Phytochemical exploration of the genus Sceletium is believed
to have commenced in 1898 when Meiring isolated a crude alka-
loid mixture from Sceletium tortuosum. This was followed by the
work of Zwicky (1914), who isolated several alkaloids including
mesembrine and mesembrenine. It is believed that plant mate-
rial of Sceletium tortuosum and Sceletium expansum was sent by
Dr. Rudolf Marloth in South Africa to Prof. C. Hartwich in Zurich.
The material was requested for E. Zwicky, a student of Prof.
Hartwich who produced a dissertation “Über channa” in 1914.
Rimington and Roets (1937) and later Popelak and Lettenbauer
(1967) suggest that the “mesembrine” described by Zwicky was
perhaps not a pure substance and corrected the molecular for-
mula for mesembrine (C16 H19 O4N) first proposed by Zwicky. The
correct formula (C17 H23NO3) was later confirmed in the early
1960’s by the well-known German pharmaceutical company C.F.
Boehringer and Soehne, and also by S.B. Penick in New York (Herre,
1971 ).
Popelak and Lettenbauer (1967) assembled all the research on
Sceletium alkaloids in their book chapter dedicated to mesem-
brine alkaloids. In this comprehensive publication they elaborate
on the isolation and synthesis of mesembrine, mesembrenine
(=mesembrenone), mesembrinol (=mesembranol) and the prob-
able artifact chinnamine. Jeffs and co-workers, based at Duke
University in North Carolina (USA), worked extensively on the
isolation and structural elucidation of Sceletium alkaloids and
reported several novel structures between 1969 and 1982. The
absolute configuration of the epimeric alcohols mesembranol and
6-epimesembranol was reported (Jeffs et al., 1969). In 1970, Jeffs
et al. reported on the isolation and structural elucidation of some
novel alkaloids from Sceletium strictum. Mesembranol (the major
alkaloid) and its acetylated derivative, 4-O-acetylmesembrenol
was isolated together with 4-O-demethylmesembrenol and 4-O-
demethylmesembranol. In addition to these new structures, pre-
viously isolated alkaloids were also mentioned, including mesem-
brine and mesembrenone. In the same year, Arndt and Kruger
reported four alkaloids from Sceletium joubertii (now reduced to
synonymy under Sceletium tortuosum). Joubertiamine represented
a new structural class different from the known mesembranes.
Joubertiamine, dehydrojoubertiamine and dihydrojoubertiamine
were all referredto as the seco-mesembranes. In the same study, the
structurally unrelated alkaloid, hordenine, wasisolated. Continuing
their work on Sceletium alkaloids, Jeff et al. (1971) reported a new
alkaloid skeleton from Sceletium namaquense.Sceletium alkaloid
A4was characterised by a 2,3-disubstituted pyridine moiety. This
structure was alluded to by Popelak and Lettenbauer (1967), and
confirmed to be the same compound described by Jeff et al. (1971).
Parallel to the publication of Jeff et al. (1971) South African scientists
also isolated and reported the structure of Sceletium alkaloid A4
together with tortuosamine, both obtained from Sceletium tortuo-
sum (Snyckerset al., 1971). In an attemptto unravel the biosynthetic
pathway of the mesembrine-type alkaloids, Jeffs et al. (1974) iso-
lated minor constituents from Sceletium namaquense (=Sceletium
tortuosum) and Sceletium strictum. From the former species, 7-
mesembrenone and N-formyltortuosamine were isolated while
4-O-demethylmesembrenone together with sceletenone were iso-
lated from Sceletium strictum. Using a combination of spectroscopic
and X-ray methods, Capps et al. (1977) resolved the structure and
absolute stereochemistry of ()-mesembrane and 3-methoxy-
4-O-methyljoubertiamine isolated from Sceletium namaquense.
Five new alkaloids were isolated from Sceletium namaquense
and described by Jeffs et al. (1982). Three compounds resemble
the joubertiamine molecule and were named 4-(3,4-dimethoxy-
phenyl)-4-[2-acetylmethylamino)ethyl]cyclohexanone, 4-(3-me-
thoxy-4-hydroxy-phenyl)-4-[2-(acetylmethylamino)ethyl]cyclo-
hexadienone and ()-3-methoxy-4-O-methyljoubertiaminol.
The structure of an unnamed alkaloid with a molecular
formula of C20H26 O3and related to Sceletium alkaloid A4
was isolated together with N-acetyltortuosamine. Working
on Sceletium subvelutinum (=Sceletium varians)Herbert and
Kattah (1990) reported joubertiamine and five derivatives of this
molecule.
The preponderance of research on Sceletium alkaloids has
revolved around isolation and structural elucidation. Very little is
known about the distribution and chemotaxonomic patterns of
these alkaloids within the genus. Comparative analytical results
for the various species are lacking. This may partially be due to
the lack of commercially available analytical reference standards.
658 N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663
Smith et al. (1996)made a valuable contribution to address this void
and elegantly summarised some ethnobotanical data and discussed
the distribution of psychoactive compounds in other genera of the
Mesembryanthemaceae. This summary was followed by a second
paper in 1998 also by Smith and co-workers in which 21 species
(representing 9 genera) of the Mesembryanthemaceae were inves-
tigated for the presence of mesembrine-type alkaloids. Due to the
lack of standards only a list of alkaloids eluting at specific retention
times were noted.
It has been mentioned in literature that the traditional method
of preparation may alter the alkaloid profile. Smith et al. (1998a,b)
mimicked the traditional fermentation process by bruising plant
material together with some soil, and sealing this in a plastic bag
for a period of time. The study reported a substantial increase
in total alkaloid yield and the GC–MS profiles indicated that the
ratios of compounds had changed during the fermentation pro-
cess. It was also reported that mesembrine levels decreased with
a corresponding increase in the levels of mesembrenone. This
Fig. 6. Structures of Sceletium alkaloids.
N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663 659
Fig. 6. (Continued ).
experiment was unfortunately carried out using different individ-
ual plants for the various experiments, so it is possible that the
results observed were due to chemotypic variation between the
plants, rather than the type of processing the material was sub-
jected to. Using a similar approach Viljoen (2007, unpublished
data) subdivided the aerial parts of a single robust plant into
three portions. The three parts were processed as follows: (1)
fresh material crushed under liquid nitrogen and transferred to
a freeze drier for 36 h, (2) fresh material crushed under liquid
nitrogen and the alkaloids immediately extracted and (3) fresh
material gently bruised and dried at 50 C for 48 h. The experi-
ment was repeated five times. The alkaloids were extracted using
an acid–base extraction method and the alkaloids were monitored
by GC–MS. Analytical pure standards of mesembrenol, mesembrine
and mesembrenone were used to confirm the identity of the vari-
ous peaks. There was no significant difference in both total alkaloid
yield as well as alkaloid ratios between the three treatments. A
similar experiment will need to be devised to establish whether
660 N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663
the traditional fermentation process, or traditional baking, does
in fact influence Sceletium alkaloids quantitatively and/or qualita-
tively.
Recently Gaffney (2006) completed a survey of alkaloids
in 15 genera of the Mesembryanthemaceae as part of a MSc
thesis. This study provides a concise and useful summary of
Sceletium alkaloids and the presence of 7 alkaloids were deter-
mined in three Sceletium species (Sceletium crassicaule,Sceletium
rigidum and Sceletium tortuosum). The major compounds in the
leaves of Sceletium tortousum were mesembrine > mesembranol >
mesembrenone > mesembrenol. Interestingly, these compounds
were not detected in the stems of the same plant.
The total alkaloid concentration in dry plant material of
Sceletium tortuosum is very variable, from 0.05 to 2.3% (Gericke,
2002). It is rather surprising that despite the rapid development
in analytical methods and the growing commercial interest gen-
erated locally and abroad in Sceletium-derived products, that the
basic information on the quantitative and qualitative composition
of alkaloids in the various species remains poorly explored. As is the
case with most natural products, alkaloids are subjected to intrinsic
and extrinsic factors which govern their production and accumula-
tion in plants. These factors have yet to be explored in Sceletium.
Furthermore, Sceletium taxonomy has remained a topic of con-
tention between modern taxonomists, challenging the taxonomic
authenticity of the species from which alkaloids have previously
been isolated. The various studies cited above clearly highlight
congruencies and anomalies in the past and present information
recorded for the various taxa emphasising the urgent need for a
thorough biosystematic study of the entire genus, and including
adequate sampling across the entire distribution range for each
species.
6. Pharmacological activity
6.1. In vitro studies
United States Patent 6,288,104 (Gericke and Van Wyk, 1999)
discloses the use of mesembrine and related compounds, includ-
ing novel compounds, as serotonin-uptake inhibitors, and the use
of standardised amounts of these compounds in pharmaceutical
formulations for use in the management of psychiatric and psycho-
logical conditions, including depression, anxiety, drug dependence,
bulimia and obsessive-compulsive disorder. Professor Alan Harvey
(pers. comm. 2008), confirmed the inhibitory activity of synthetic
()-mesembrine on the serotonin transporter (Fig. 7). The inhibi-
Fig. 7. Mesembrine activity on monoamine uptake. The graph illustrates that
mesembrine selectively inhibits the uptake of serotonin (5-HT), with limited
inhibition of noradrenalin-uptake and dopamine-uptake at much higher concentra-
tions. (By kind permission of Professor Alan Harvey, Strathclyde Institute for Drug
Research. The synthetic ()-mesembrine used in this study was prepared by Dr
Douglass F. Taber of the Chemistry Department, University of Delaware.).
tion of serotonin reuptake may be one of the possible mechanisms
whereby ingestion of adequate doses of Sceletium can influence
mood and anxiety states, and quality of sleep. Fig. 7 illustrates that
mesembrine selectively inhibits the uptake of serotonin (5-HT),
with limited inhibition of noradrenalin-uptake and dopamine-
uptake at much higher concentrations.
Mesembrine-HCl has been demonstrated to be an inhibitor of
phosphodiesterase-4 (PDE4) at an IC50 of 29 microM. (Napoletano
et al., 2001). Cyclic AMP (cAMP) is a key second messenger com-
partmentalized within all cells, and cAMP signaling is influenced by
approximately 20 subtypes of the PDE4 family. The selective inhibi-
tion of this family of enzymes generates profound functional effects
and PDE4 inhibitors are currently drug targets for novel therapeu-
tics for the treatment of inflammatory diseases, including asthma,
chronic obstructive pulmonary disease, psoriasis, as wellas treating
depression (Houslay et al., 2005).
Mesembrenone has been found to have cytotoxic activity against
a murine non-tumoral fibroblast cell line and a human tumoral
cell line (Molt4). Of 25 isolated Amaryllidaceae alkaloids tested,
only mesembrenone showed some specificity against Molt4 cells
in comparison to the fibroblast cells (Weniger et al., 1995).
6.2. In vivo studies
6.2.1. Historical
In 1889, Meiring injected an alkaloidal principle from Sceletium
tortuosum into the skin of a frog, resulting in a marked hypnotic
effect. Meiring later isolated alkaloid mixture from Sceletium tor-
tuosum, and injected one to two drops under the skin of a frog
resulting in an apparent effect within a few minutes, including rapid
respiratory rate, marked moistness of skin, and uneasiness. After
10–12 min the respiratory rate became very slowed, and although
the frog remained conscious, it could not right itself when placed on
its back. Full recovery took place after 4–8 h. These resultsrepresent
the average seen in a number of experiments with frogs, although
in some cases the frog died. Meiring noted that even with a 10-fold
increase in the dose used in frogs, the effect in guinea pigs was mild,
with only uneasiness and refusal of food being noted. However, one
guinea pig died 24 h later, while a second was fully recovered after
24 h ( Meiring, 1898).
Watt and Breyer-Brandwijk (1962) report Zwicky’s contradic-
tory assertion from his research in 1914 that isolated mesembrine
had a “cocaine-like activity”, although weaker in action, and yet
stated that it produced depression of the central nervous system
in the frog, the rabbit, and man, rather than the stimulation one
would expect from a cocaine-like action.
6.2.2. Safety
Hirabayashi et al. (2002) reported a safety study of Sceletium
tortuosum administration to canines. Milled dry Sceletium tor-
tuosum was given at a dose of 10 mg/kg twice a day to seven
healthy beagle dogs, as well as one dog with dementia for 6
days. The plant material was mixed into the animals’ food. Pre-
and post-feeding observations and blood tests were made, includ-
ing red cell count, haemaglobin, haematocrit, white cell count,
platelet count, blood urea nitrogen, creatinine, glucose, glutamic-
pyruvic transaminase, total cholesterol, and total protein. Holter
monitoring of the ECG was done for the duration of the study.
No changes in behaviour were noted in the healthy dogs, and
there was no vomiting or diarrhoea. The blood tests showed no
changes that could suggest abnormality in the haematology, liver
and kidney functions, glucose, or lipid metabolism over the 6-
day period. No adverse effects were noted in the dog suffering
from dementia. There were no cardiac arrhythmias, and there
were no adverse effects on cardiac function. It was concluded
N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663 661
that Sceletium tortuosum can be given safely to canines at this
dose.
Hirabayashi et al. (2004), reported a safety study in cats. Six
healthy cats aged from 2 to 10 years were given 100 mg/kg milled
Sceletium tortuosum once a day for 7 days. Blood was taken before
the study, and at the end of the study, for full blood count,
platelets, urea, creatinine, glucose, total protein, total cholesterol,
ALP (alkaline phosphatase), CPK (creatine phosphokinase), GPT
(glutamate-pyruvic transaminase), and GOT (glutamic oxaloacetic
transaminase). Measurement of body weights and body tempera-
tures were done before and after the drug administration. During
the administration period, general aspects were monitored, includ-
ing appetite, vitality, excretion, and behavior. No adverse effects,
including any diarrhoea or vomiting were observed during the
observation period. A slight increase in daytime sleep was noted.
In the case of blood chemistry, a slight decrease of GOT (glutamic
oxaloacetic transaminase) and increase of ALP (alkaline phos-
phatase) were observed, however, these differences were within
normal limits. No other changes were observed in blood count,
blood chemistry, body weight or body temperature.
6.2.3. Efficacy
Hirabayashi et al. (2002) reported an efficacy study on Sceletium
tortuosum administered to canines. Milled dry Sceletium tortuo-
sum was given at a dose of 10 mg/kg once daily, in the evening, to
seven dogs suffering from dementia for 6 days. The dogs had been
diagnosed with dementia after having been brought to an animal
hospital for incessant barking at night. The animals were treated as
outpatients, after the owners had been instructed on how to mix the
Sceletium into the dogs’ food, and how to observe for any adverse
signs or symptoms. In all the study animals the barking at night
either decreased significantly, or resolved completely. This study is
preliminary evidence of the efficacy of Sceletium tortuosum for the
alleviation of excessive night-time barking in dogs diagnosed with
dementia.
Hirabayashi et al. (2004) reported on five case studies of cats
treated by veterinarians with Sceletium tortuosum forarangeof
problems, including tow cats with cage-stress in a cattery, one cat
with travel-stresswhile traveling by car, one cat with excessive noc-
turnal meowing, and one cat with inadequate depth of anaesthesia
for a denatk procedure from medetomidine as a sole anaesthetic.
Ketamine could not be used as a co-anaesthetic in the latter animal.
Doses of between 10 and 100 mg/kg of Sceletium tortuosum were
administered, from single doses to daily doses for up to 6 months
duration. Significant calming activity was notedin the two cats with
cage-stress as well as in the cat with travel-stress, with a duration
of action of 6–10h after a single dose of Sceletium. The cat with
excessive nocturnal meowing was well-controlled, and during the
6-month period of administration of Sceletium, no adverse effects,
such as anorexia, diarrhoea or vomiting was observed. In the cat
requiring anaesthesia for teeth-scaling, a single dose of Sceletium
at 60 mg/kg administered before the medetomidine, kept the cat
recumbent, with no physical restraint necessary.
Hirabayashi et al. (2005) reported on the treatment with
Sceletium of 31 dogs and 2 cats with clinical signs of dementia.
All the animals were companion animals rated by the researchers
having various degrees of dementia assessed by a dementia rat-
ing score. A key symptom in the dogs was uncontrolled nocturnal
barking, and in the cats excessive nocturnal crying. Sceletium was
owner-administrated as a single dose, once at night. Doses rang-
ing from 2 to 90 mg/kg were given, and the duration of treatment
ranged from 5 to 183 days.
The efficacy assessment was done by the owners of the com-
panion animals. The most effective doses were those greater than
30 mg/kg, and cessation of barking was fairly rapid, within took
30 ±20 min. All animals except one showed some efficacy, and
owners were satisfied with the results in 61% of the cases, includ-
ing 8 remarkably effective cases, and 12 moderately effective cases.
No adverse effects were noted, including at the very high dose of
90 mg/kg, or for the long duration of 183 days. A dose–response was
noted. A reduction in efficacy noted after continuous use could be
reversed by a 2-day break.
6.2.4. Anecdotal/clinical data
The physician and botanist CarlWilhelm Ludwig Pappe reported
that farmers use Sceletium tortuosum in the form of a decoction or
a tincture, as a good sedative (Pappe, 1868). Isaac Meiring reported
“some clinical experiments with a tincture of the dried plant [of
Sceletium tortuosum] proved that it had decided anodyne [i.e. anal-
gesic] properties without concomitant bad effects” (Meiring, 1898).
In 1914, Zwicky chewed 5g of kougoed resulting in nausea, anal-
gesia to the mouth, normal pulse, discomfort and stuffiness of the
head, and loss of appetite. On a separate occasion he swallowed
a decoction made from 15g of kougoed, with similar results, but
including headache, and the local anaesthetic action was found to
be much weaker than cocaine (Watt and Breyer-Brandwijk, 1962).
Smith et al. (1996) reported the effect in two individuals of 2 g
of kougoed held in the mouth with a small quantity of alcohol.
A feeling of “tranquil mellowness” was experienced after 30 min,
with no impairment of motor function, and no hallucinations. On
a later occasion these same individuals took 1g material, which on
this occasion the material included root. The subjects experienced
the same effect as before, but stronger. The effects of traditionally
prepared kougoed was documented by Smith et al. (1996), and a
wide range of effects were reported, including anxiolytic activity,
improved social intercourse, decreased self-consciousness, syner-
gistic effect with alcohol and with Cannabis, decreased substance
abuse in poly-substance abuser, as well as feelings of relaxation,
and a meditative state of mind. Three first-time users reported
clouding of consciousness with doses that were high enough to be
intoxicating. Ingestion of Sceletium gave pain relief from a bee-sting.
Gericke (2002) reports that when taken in intoxicating doses,
Sceletium tortuosum can cause euphoria, initially with stimulation,
followed by sedation, but the plant is not hallucinogenic, and no
severe adverse effects are known. Chronic use does not appear
to result in a withdrawal state. Tinctures of the plant are useful
clinically for treating anxiety, depression and stress.
6.2.5. Clinical case reports
Gericke (2001) reported on three case studies where Sceletium
tortuosum in tablets and capsules had been prescribed or recom-
mended by a general practitioner, a psychologist, and a psychiatrist,
respectively. In the first case, the patient, a medical doctor, was
suffering from severe depression of 4 months duration, with poor
appetite, weight loss, insomnia, decreased energy and drive, anx-
iety, emotional liability and suicidal ideation. The patient was
started on a tablet of 50mg Sceletium daily. The patient initially
reported a transient increase in anxiety after taking medication,
which would last up to 3h, but was no longer apparent after
the first week of treatment. A sustained improvement in mood
was reported, with a marked decrease in generalised anxiety. The
patient’s insomnia improved at the onset of treatment. This low
dose of Sceletium proved to be an effective anxiolytic and mood-
elevator in this patient. The Sceletium was discontinued after 4
months of continual use with no signs or symptoms of withdrawal.
In the second case, a patient with a personality disorder was
diagnosed as suffering from dysthymia by her psychologist. The
patient felt despondent, socially withdrawn, felt tearful and empty,
and had a feeling of pervasive sadness. There was no suicidal
ideation, but mood was depressed alternating with anxiety, and
662 N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663
there was loss of motivation and interest, with hypersomnia. In
addition to ongoing therapy, Sceletium was recommended as a
tablet of 50 mg daily. Within 10 days the patient said that her mood
had lifted, and she was able to feel more focused, more engaged
and not so socially “distant”. She doubled her dose of Sceletium to
two 50 mg tablets daily just prior to her exams a month later, and
described feeling less anxious and more able to cope with her usual
examination anxiety. An interesting development on Sceletium was
that the client described feeling less inclined to over-indulge in
alcohol. The conclusion was made that while the client had per-
sonality problems that required ongoing therapy, the Sceletium had
helped her feel more contained, had lifted her mood, and had also
helped with the anxiety.
In the third case, the patient presented with Major Depressive
Disorder, with symptoms of depressed mood, increased sleep, over-
eating, anxiety, psychomotor agitation, and thoughts of death. The
patient had initially attempted self-medication with a St. John’s
Wort (Hypericum perforatum) product over the preceding 2 weeks,
with minimal effect. The patient was started on Sceletium,50mgin
the morning and at lunchtime. On the first day of Sceletium treat-
ment the patients mood felt lifted, and her sleep pattern improved
from an excess of 14 h sleep a day to 8h a day. The patient reported
an increase in energy and was able to spontaneously resume her
housework. After 6 weeks of treatment with Sceletium togetherfully
recovered and was maintained.
7. Concluding comments
Although Sceletium tortuosum has so far received the most
attention among the Sceletium species both for research and com-
mercial development, it is clear that other species of Sceletium were
certainly utilized in the past, including Sceletium emarginatum,
Sceletium expansum, and Sceletium strictum. With further research,
these species may also prove to be suitable candidates for prod-
uct development. It is not yet apparent what the relative advantage
would be of one species over another.
Sceletium species have enjoyed a wide range of uses: as masti-
catory, tea, relief of hunger, thirst, and fatigue, restorative, sedative,
hypnotic, analgesic, antispasmodic, and mood-elevator, through to
intoxicant. The spectrum of uses are likely to be dose-dependent,
with the lowest doses of active alkaloids at the simple masticatory
side of the spectrum of uses, and the highest doses at the intoxicat-
ing end of the spectrum. It is instructive that elderly rural users of
kougoed in Namaqualand remove the quid of Sceletium well before
any intoxication is experienced, and it is common to re-use the
same piece of chewing material as and when they feel like it. This
traditional use as a simple masticatory would seem to suggest that
very little alkaloid is in fact ingested or absorbed.
Sceletium is used as fresh plant material, baked fresh plant mate-
rial, dried plant material, and dried “fermented” plant material. In
some cases the entire plant is used, and in other the roots are first
removed. With our present knowledge of the chemistry and biolog-
ical activities of Sceletium it is not yet clear what the qualitative and
quantitative phytochemical differences are between each of these
forms of the raw material. Local users do say that the tradition-
ally processed material is more powerful, in terms of intoxication
potential, so that this processing may not be necessary for raw
material intended for other uses. Howeverwe do not yet know what
microbiological, enzymatic, or chemical processes occur during the
“fermentation” or what affect this traditional processing has on the
chemistry or biological activities in the raw product.
Manufactured Sceletium tortuosum products have increasingly
been appearing on the market as natural supplement for stress,
tension, low mood, and for treating anxiety and depression. The
products are typically tinctures, tablets or capsule where the unit
doses recommended in these products tend to be in the range from
50 to 200 mg of dried milled herbal material. Sceletium raw material
is very variable in total alkaloid content, with the highest values
being around 2% of the dry weight. Thus the highest doses of total
alkaloid per unit dose of commercial products could be within the
range of about 1–4mg (Van Wyk and Wink, 2004).
The well-established history of use of Sceletium, extant long-
term local use, and increasing use of manufactured Sceletium
products with no known severe adverse effects, suggests that
Sceletium is safe for human consumption. This is further sup-
ported by the documented safety in dogs treated with 10 mg/kg
Sceletium given twice daily (Hirabayashi et al., 2002) and cats
treated with 100mg/kg per day (Hirabayashi et al., 2004), and dogs
with dementia treated with up to 90 mg/kg per day. (Hirabayashi et
al., 2005). These doses are far higher than the dose of approximately
1–2 mg/kg per day that humans typically ingest in the form of
tablets or capsules. Animal studies (Hirabayashi et al., 2004, 2005)
indicate potential veterinary applications for Sceletium, including
sedative for cage-stress and travel-stress, and treatment of exces-
sive nocturnal barking in dogs and crying in cats.
The in vitro activity of mesembrine and related compounds as
serotonin-uptake inhibitors provides preliminary pharmacologi-
cal support for the use of Sceletium in products for stress, anxiety
and depression, and may also provide a rationale for the appar-
ent lack of dependence seen with long-term Sceletium use. The in
vitro activity of mesembrine as a PDE4 inhibitor is another mecha-
nism whereby Sceletium may act as an antidepressant, and suggests
additional therapeutic potential. The pharmacological study of
Sceletium is still in its infancy, however, and a great deal of work
remains to be done. We do not yet know whether these two activ-
ities will also be found for other Sceletium alkaloids, and if so,
which compounds will have the most potent and selective activ-
ities. While the focus of pharmacological research for over 100
years has been on the alkaloids, the non-alkaloid components have
been neglected, and may provide an entirely new field for Sceletium
research.
It is hoped that formal placebo-controlled clinical studies on
standardised Sceletium products will be undertaken to formally
establish safety and efficacy, so that the great potential of this plant
to assist people living with anxiety and depression and other health
conditions can be realized.
Acknowledgments
The following individuals and institutions are thanked for their
invaluable contribution; The South African Museum for permis-
sion to photograph and reproduce the painting of Sceletium in
the collection known as the Codex Witsenii. Cornelia Klak at the
Bolus Herbarium for comments on the taxonomy and nomencla-
ture and Lyndy McGaw for sourcing dated literature in the library
at Onderstepoort, David Gordon for providing a copy of his paper
“From rituals of rapture to dependence: the political economy
of Khoikhoi narcotic consumption”, Anne Digby for providing a
copy of her paper “Self-medication and the Trade in Medicine
within a multi-ethnic context: A case study of South Africa from
the mid-nineteenth to mid-twentieth Centuries”, Edda Fiegert for
hard work in sourcing a copy of Hartwich and Zwicky (1914),
Olga Gericke for translating Hartwich and Zwicky (1914), Alan
Harvey for providing the graph (Fig. 7) on the effect of synthetic
mesembrine on monoamine uptake, Satoru Furukawa for provid-
ing copies and translations of the Japanese papers Hirabayashi
et al. (2002),Hirabayashi et al. (2004), and Hirabayashi et al.
(2005).
N. Gericke, A.M. Viljoen / Journal of Ethnopharmacology 119 (2008) 653–663 663
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... Of the eight species in the genus, only S. tortuosum (commonly known as "kougoed", "kanna" or "channa") is used in the emergent phytopharmaceutics industries in South Africa and this use stems from the ethnobotany of the Khoi-San. The plant has been administered in a dried or fermented form for traditional uses ranging from pain and thirst relief to mood elevation (1). The mood-elevating activity of S. tortuosum has been attributed to the mesembrine alkaloids (particularly mesembrine and mesembrenone), acting as serotonin reuptake inhibitors (2), amongst other observed activities. ...
... With this in mind, we chose to also explore molecular networking as a dereplication tool. Metabolomics paired with molecular networking may assist in distinguishing populations from each other with a great deal of phytochemical detail, especially where the chemistry is still largely unresolved (1). The feature identification capabilities of molecular networking act as a dereplication tool through identifying coeluting isobaric compounds and reducing redundancy by identifying isomers across samples from MS 2 fragmentation patterns (14). ...
... This is the first evidence put forward that minor alkaloids may be responsible for neurological activity observed in vitro. Current reports where isolated extracts have negligible activity as compared to extracts may suggest other phytochemicals responsible for the mood-elevation and cognitive enhancement activity in Sceletium (1,22). Further in vitro and in vivo studies would have to be conducted on isolated metabolites to corroborate these findings. ...
Article
Full-text available
The Sceletium genus has been of medicinal importance in southern Africa for millennia and Sceletium tortuosum (Aizoaceae), one of eight species in the genus has gained pharmaceutical importance as an anxiolytic and anti-depressant due to the presence of mesembrine alkaloids. S. tortuosum is used for the manufacture of herbal teas, dietary supplements and other phytopharmaceutical products. This study aimed to provide a metabolomic characterization of S. tortuosum and its sister species as these are not easy to distinguish using morphology alone. Plant samples were thus collected from various locations in the succulent Karoo (South Africa) and analyzed through liquid chromatography-mass spectrometry (LC-MS), using MS E fragmentation as a putative tool for chemical identities. Metabolomics-based analyses in combination with molecular networking were able to distinguish between the four species of Sceletium based on the presence of 4-(3,4-dimethyoxyphenyl)-4-[2-acetylmethlamino)ethyl]cyclohexanone ( m/z 334.2020; RT 6.60 min), mesembrine ( m/z 290.1757; RT 5.10 min) and 4'-O-demethylmesembrenol ( m/z 276.1597; RT 4.17 min). Metabolomic profiles varied according to the different localities and metabolites occurred at variable quantitative levels in Sceletium ecotypes. Molecular networking provided the added advantage of being able to observe mesembrine alkaloid isomers and coeluting metabolites (from the joubertiamine group) that were difficult to discern without this application. By combining high-throughput metabolomics together with global and feature based-molecular networking, a powerful metabolite profiling platform that is able to discern chemical patterns within and between populations was established. These techniques were able to reveal chemotaxonomic relationships and allowed for the discovery of chemical markers that may be used as part of monitoring protocols during the manufacture of phytopharmaceutical and dietary products based on Sceletium .
... Mesembryanthemum tortuosum L. (Aizoaceae) is a succulent plant indigenous to the southwestern parts of South Africa (Loria et al., 2014) and is of scientific interest due to its possible therapeutic effects, such as the enhancement of physical well-being and the treatment of anxiety, stress, and depression (Gericke and Viljoen, 2008). Traditionally, pastoralists and hunter-gatherers have used this plant for managing mood-swings and improving general well-being (Van Wyk and Gericke, 2000). ...
... Mesembryanthemum tortuosum, known as 'kougoed' or 'channa' in South Africa, traditionally used for its tranquillizing and anxiolytic properties (Gericke and Viljoen, 2008;Smith, 2011), is marketed as Zembrin®, a standardized ethanolic extract (Shikanga et al., 2012). Since 2010 M. tortuosum has been the subject of much in vitro and in vivo research, as well as clinical studies, with respect to its CNS activity. ...
... Since 2010 M. tortuosum has been the subject of much in vitro and in vivo research, as well as clinical studies, with respect to its CNS activity. All these studies, with the exception of Fountain (2016), corroborated its mood elevation, antidepressant or antiepileptic activity (Gericke and Viljoen, 2008;Harvey et al., 2011;Loria et al., 2014;Schell, 2014;Carpenter et al., 2014;Dimpfel et al., 2018). The anxiolytic-like effects of M. tortuosum have also been studied and substantiated by some research groups (Dimpfel et al., 2018;Fountain, 2016). ...
Article
Ethnopharmacological relevance Mesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. Aim of the study To investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. Materials and methods Locomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. Results All four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. Conclusions M. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic.
... (Aizoaceae) commonly called "kanna" or "kougoed", is a succulent medicinal herb indigenous to South Africa (Carpenter et al., 2016). Aerial parts of the plant are commonly masticated or chewed, taken as tea or tincture, and occasionally smoked (Gericke and Viljoen, 2008). The plant is chewed for the relief of abdominal pain, toothache, and hunger, and fresh juice from the plant is given to induce sleep in young children (Gericke and Viljoen, 2008). ...
... Aerial parts of the plant are commonly masticated or chewed, taken as tea or tincture, and occasionally smoked (Gericke and Viljoen, 2008). The plant is chewed for the relief of abdominal pain, toothache, and hunger, and fresh juice from the plant is given to induce sleep in young children (Gericke and Viljoen, 2008). It is currently used commercially to treat different central nervous system (CNS) related disorders, including stress, depression, and anxiety (Yin et al., 2019). ...
... Over two decades ago, Smith et al. (1996), published the first ethnopharmacological review on the genus Sceletium and more than a decade later, in 2008, Gericke and Viljoen (2008), published the second review focusing on the chemistry, pharmacology, clinical and veterinary applications of Sceletium, with much emphasis on S. tortuosum. Gericke (2018) provided a review of the historical uses, ethno-pharmacology and pre-clinical studies of Zembrin® and quite recently, a review was published on the biological and pharmaceutical properties of S. tortuosum (Manganyi et al., 2021). ...
... (Aizoaceae) commonly called "kanna" or "kougoed", is a succulent medicinal herb indigenous to South Africa (Carpenter et al., 2016). Aerial parts of the plant are commonly masticated or chewed, taken as tea or tincture, and occasionally smoked (Gericke and Viljoen, 2008). The plant is chewed for the relief of abdominal pain, toothache, and hunger, and fresh juice from the plant is given to induce sleep in young children (Gericke and Viljoen, 2008). ...
... Aerial parts of the plant are commonly masticated or chewed, taken as tea or tincture, and occasionally smoked (Gericke and Viljoen, 2008). The plant is chewed for the relief of abdominal pain, toothache, and hunger, and fresh juice from the plant is given to induce sleep in young children (Gericke and Viljoen, 2008). It is currently used commercially to treat different central nervous system (CNS) related disorders, including stress, depression, and anxiety (Yin et al., 2019). ...
... Over two decades ago, Smith et al. (1996), published the first ethnopharmacological review on the genus Sceletium and more than a decade later, in 2008, Gericke and Viljoen (2008), published the second review focusing on the chemistry, pharmacology, clinical and veterinary applications of Sceletium, with much emphasis on S. tortuosum. Gericke (2018) provided a review of the historical uses, ethno-pharmacology and pre-clinical studies of Zembrin® and quite recently, a review was published on the biological and pharmaceutical properties of S. tortuosum (Manganyi et al., 2021). ...
Article
Ethnopharmacological relevance Sceletium tortuosum (L.) N.E.Br., the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. Aim of the review The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological, pre-clinical and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. Methods All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. Results Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, neuromodulatory, immunomodulatory, anti-HIV, neuroprotection) in in vitro or in vivo studies. While the plant has been studied in clinical populations, this has only been in healthy subjects, so that further study in pathological states remains to be done. Nevertheless, the aforementioned studies have demonstrated that S. tortuosum has potential for enhancing cognitive function and managing anxiety and depression. Conclusion As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.
... A number of potential mechanisms for its observed clinical effects have been described. The main active constituents have been identified as mesembrine alkaloids and some of their individual properties have been investigated [1][2][3]. ...
... In 1738, Kolben noted kanna (or channa) to be the "greatest Chearer of the Spirits, and the noblest Restorative in the World" [12]. In 1924, Kolben was referencing a plant used by the Khoi for enjoyment, which they "chewed, kept in their mouth for some time, thus becoming excited…" [1]. The traditional use as masticatory is also described by Commelin in 1692 [13], Thunberg ca. ...
... The traditional use as masticatory is also described by Commelin in 1692 [13], Thunberg ca. 1770 [4], and numerous other sources [1,6,12,[14][15][16][17][18][19][20][21][22][23]. ...
Article
Modern-day regulatory systems governing conditions for how health products enter national markets constitute a barrier of access for traditional herbal medicines on an international level. Regulatory intentions are focused on ensuring consumers are being provided with safe, efficacious and high-quality products that, however, collaterally limit opportunities for traditional herbal medicinal products, especially those that do not already have a long-standing tradition of use established in the respective national marketplaces. This case study investigates and compares how a Southern African herbal medicine with great potential as an anxiolytic and mild antidepressant – Mesembryanthemum tortuosum L. [syn. Sceletium tortuosum (L.) N.E.Br.] aerial parts – fares internationally in today’s regulatory environments. It is argued that inadvertent regulatory favoritism combined with the lack of means for adequate protection of intellectual property may obstruct innovation by creating an almost insurmountable economical hurdle for successful product development and introduction of botanicals from developing countries into most of the world’s health product markets.
... For generations, the indigenous Khoisan people have used ST as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects (Gericke and Viljoen, 2008;Brendler et al., 2021). The characteristic alkaloid profile of Sceletium tortuosum, including mesembrine, mesembrenone, mesembrenol, and mesembranol (Krstenansky, 2017), presents with subtly different neuro-psycho-pharmacological actions (Olatunji et al., 2021) that may underlie the above-mentioned therapeutic properties. ...
... In vitro studies by Harvey et al. (2011) andZhong et al. (2012) suggest that ST shares some mechanistic properties of SSRIs as both target 5-HT through potent inhibition of SERT (Harvey et al., 2011;Brendler et al., 2021). In fact, alkaloid components of ST, specifically mesembrine, mesembrenol and mesembrenone, present with dose-dependent inhibitory actions on SERT, similar to that of citalopram and fluoxetine (Coetzee et al., 2016;Gericke and Viljoen, 2008;Krstenansky, 2017). ST also possesses monoamine releasing properties by increasing VMAT-2 and is also a mild MAO-A inhibitor (Coetzee et al., 2016;Gericke and Viljoen, 2008;Krstenansky, 2017). ...
... In fact, alkaloid components of ST, specifically mesembrine, mesembrenol and mesembrenone, present with dose-dependent inhibitory actions on SERT, similar to that of citalopram and fluoxetine (Coetzee et al., 2016;Gericke and Viljoen, 2008;Krstenansky, 2017). ST also possesses monoamine releasing properties by increasing VMAT-2 and is also a mild MAO-A inhibitor (Coetzee et al., 2016;Gericke and Viljoen, 2008;Krstenansky, 2017). Although not immediately evident with respect to the actions of Zembrin® on serotonergic-based swimming behaviour (Fig. 3B), ESC and Zembrin® can broadly be regarded as serotonergic drugs, indirectly activating pre-and post-synaptic 5-HT 1A and 5-HT 2A/C receptors via SERT inhibition. ...
Article
Ethnopharmacological relevance Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. Aim of the study To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. Materials and methods The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. Results Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. Conclusions Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.
... (Aizoaceae) commonly called "kanna" or "kougoed", is a succulent medicinal herb indigenous to South Africa (Carpenter et al., 2016). Aerial parts of the plant are commonly masticated or chewed, taken as tea or tincture, and occasionally smoked (Gericke and Viljoen, 2008). The plant is chewed for the relief of abdominal pain, toothache, and hunger, and fresh juice from the plant is given to induce sleep in young children (Gericke and Viljoen, 2008). ...
... Aerial parts of the plant are commonly masticated or chewed, taken as tea or tincture, and occasionally smoked (Gericke and Viljoen, 2008). The plant is chewed for the relief of abdominal pain, toothache, and hunger, and fresh juice from the plant is given to induce sleep in young children (Gericke and Viljoen, 2008). It is currently used commercially to treat different central nervous system (CNS) related disorders, including stress, depression, and anxiety (Yin et al., 2019). ...
... Over two decades ago, Smith et al. (1996), published the first ethnopharmacological review on the genus Sceletium and more than a decade later, in 2008, Gericke and Viljoen (2008), published the second review focusing on the chemistry, pharmacology, clinical and veterinary applications of Sceletium, with much emphasis on S. tortuosum. Gericke (2018) provided a review of the historical uses, ethno-pharmacology and pre-clinical studies of Zembrin® and quite recently, a review was published on the biological and pharmaceutical properties of S. tortuosum (Manganyi et al., 2021). ...
Article
Ethnopharmacological relevance Sceletium tortuosum (L.) N.E.Br, the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, and as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. Aim of the review The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. Methods All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. Results Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, immunomodulatory, anti-HIV, neuroprotection, enhancement of cognitive function) in in vitro or in vivo studies. This plant has not yet been studied in a clinical population, but has potential for enhancing cognitive function, and managing anxiety and depression. Conclusion As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.
... Sceletium tortuosum (sold as a standardized extract under the name Zembrin ® (ZEM)) is a succulent plant native to the South African region [1]. In traditional folk medicine, leaves from the plant have been chewed or used in teas and implicated in the amelioration of thirst, staving hunger, and decreasing fatigue [2]. As of late, ZEM has been identified as a promising nutraceutical with potent anxiolytic and anti-depressant actions [3,4]. ...
Article
Full-text available
The purpose of this study was to investigate acute Zembrin® (Sceletium tortuosum) supplementation on muscle soreness, markers of muscle damage, mood, and exercise performance following unaccustomed resistance exercise. Untrained females (n = 16) were divided into two groups with a different three-day treatment regimen: (1) placebo (PL) and (2) Zembrin® (ZEM). During the initial visit, baseline perceived soreness, range of motion (ROM), mood state (profile of mood states (POMS) questionnaire), and plasma lactate dehydrogenase concentrations (LDH) were measured followed by the performance of an eccentric bicep curl protocol with their non-dominant arm. The total repetitions and rate of perceived exertion (RPE) were recorded throughout the exercise. The participants then supplemented with the corresponding treatment immediately following, the subsequent day, and 30 min prior to completing a 48 h follow-up visit. For the 48 h visit, all procedures were repeated and comparisons were drawn for perceived soreness, ROM, LDH, mood scores, total repetitions, and RPE. The findings indicate that short-term ZEM supplementation resulted in lower perceived soreness (p = 0.020) and a greater preservation of ROM (p = 0.028) at 48 h versus the PL group. Mood worsened from the baseline to 48 h regardless of the treatment (p = 0.043) but the decrements were exacerbated in the PL group compared with the ZEM group (p < 0.001). LDH levels (p = 0.019) and RPE (p = 0.008) were higher and total repetitions were lower (p < 0.001) at 48 h irrespective of the treatment. Although short-term dietary enrichment with ZEM did not alter the exercise performance or biomarkers of muscle damage, the current results suggest ZEM supplementation may be effective in reducing the markers of soreness and preserve mood following unaccustomed eccentric exercise.
Article
Different routes of access to mesembrine alkaloids uniquely produced by the medicinal succulent Sceletium tortuosum (Aizoaceae) are thus highly sought after in the natural products sector. In order to develop a biotechnological method, the establishment of in vitro microshoot and callus suspension cultures was investigated using in vitro seedlings of S. tortuosum. The production of mesembrine and other alkaloid derivatives in vitro was monitored using high-throughput ultra-high performance liquid chromatography-mass spectrometry in regenerated microplant and callus cultures. Microshoots were transferred to a shoot multiplication medium after initiation on media with factorial combinations of 1-naphthylacetic acid and N⁶-benzyladenine at 0–1 mg/L and 1–5 mg/L, respectively. Persistent carryover effects associated with the initiation procedures led to four dominant morphotypes. A drier Micropore™ seal environment reduced the number of propagules but the cultures exhibited greater proportions of healthy plantlets (88%) even though the incidence of a red coloured pigment was higher, recorded at 100% in some of the lines. Using a semi-in vitro technique, 96% of in vitro derived plants survived ex vitro. Microshoot cultures, pre-treated with a dehydration step, accumulated four key biomarkers with mesembrine (3270.9 mg/kg), mesembranol (4738.8 mg/kg), mesembrenol (333.1 1 mg/kg), and Δ⁴- mesembrenone (29.9 mg/kg) (dry weight) at levels comparable to wild types. Δ⁷-Mesembrenone, while detected in the microshoots, was not present in callus cultures. The reported mass propagation strategies are opportune for offering an alternative source to the mesembrine alkaloids currently used in clinical herbal formulations.
Article
Asymmetric total synthesis of (−)-sila-mesembranol, the silicon analog of the natural alkaloid (−)-mesembranol has been achieved in 3.3% yield over 11 steps. The chiral silicon center was enantioselectively constructed via...
Patent
Full-text available
There is disclosed the use of mesembrine and related compounds (e.g. mesembranol, mesembranone) as scrotonin-uptake inhibitors, pharmaceutical compositions comprising such compounds or dry material or an extract of plants from the Mesembryanthemaceae family (e.g. Sceletium Sceletium (Aizoaceae) tortuosum) containing a standardized content of said compounds, for use in the treatment of depressive states, psychological or psychiatric disorders with an anxiety component, alcohol and drug dependence, bulimia nervosa and obsessive-compulsive disorders. Also disclosed are new derivatives of mesembrine.