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abstract
Part I
The history of the use of kanna, the traditionally used plant material derived from a number of
Sceletium species, is given from 1610-1971. This overview includes fragments of history document-
ing European ships docking in the Cape to search for kanna roots as a “ginseng” to trade in the
Far East, and an ethnographic record from the 1700s transcribed directly from //Kabbo, a /Xam San
“Bushman” from the Breakwater Convict Station in Cape Town, who gave us the name !k”waï for
kaauwgoed, the Dutch name for kanna, and his own account of the uses of the plant.
Flower of a low-mesembrine Sceletium cultivar.
Kabbo’s !Kwaiń: The Past, Present
and Possible Future of Kanna
Founding Director of HG&H
Pharmaceuticals (Pty), Ltd.,
Bryanston, South Africa
Nigel Gericke, MD
122
Gericke, N. Kabbo’s !Kwaiń: The Past, Present and Possible Future of
Kanna, pp. 122-150, in McKenna, D. et al. (Eds.) 2018. The
Ethnopharmacological Search for Psychoactive Drugs. Synergetic Press,
Santa Fe. ISBN-13: 978-0907791683
Nigel Gericke
Part II
The recent ethnobotany, ethnopharmacology and pre-clinical research on a commercialized
standardized extract of Sceletium (trademarked Zembrin®) is given for the period 1995 to 2017. In
vitro studies have demonstrated that the major alkaloids of kanna, including mesembrine, mesem-
brenone and mesembrenol, are responsible for the psychoactivity of Sceletium, and have dual se-
rotonin reuptake inhibitory (SRI) activity and phosphodiesterase-4 (PDE4) inhibitory activity. The
effect of the extract of Sceletium tortuosum, Zembrin®, on brain electrical activity has been studied
in vivo, demonstrating by discriminant analyses that the quantitative EEG electropharmacogram
of the extract plots in close proximity to the plots for Ginkgo biloba, Rhodiola rosea, and also to the
first-generation pharmaceutical PDE4 inhibitor Rolipram, indicating the potential of this extract
for managing anxiety and depression and enhancing cognitive function.
Part III
Clinical experience with Sceletium is summarized and the results of pilot randomized, dou-
ble-blind, placebo-controlled clinical studies on the extract of Sceletium tortuosum, Zembrin®, are
presented, including:
• A safety and tolerability study.
• A pharmaco-Magnetic Resonance Imaging study.
• A study on cognitive function domains using CNS Vital Signs, a computerized neu-
rocognitive test battery.
• A study looking at changes in brain electrical activity in response to cognitive and
emotional challenges; changes in psychometric tests; and changes in the Hamilton
Anxiety Scale (HAM-A).
Part IV
Scenarios on the future of kanna and alkaloids derived from kanna are considered.
Folk names for traditionay used Sceletium species
kanna Nama-speaking Khoikhoi people. Sometimes also written canna and channa.
kougoed Afrikaans-speaking people of European or mixed descent, derived from the
earlier Dutch kaauwgoed or kauwgoed, meaning “chewing stuff.”
!k”waï Also !k”wai:n. /Xam-speaking San people. is language is now extinct.
botany
The genus Sceletium of the Family Aizoaceae, Mesembryanthemoideae, is characterized by
the distinctly skeletonized leaf venation visible in dried older leaves. Sceletium is a genus with a
climbing, or decumbent, habit and succulent leaves that sometimes have prominent idioblasts, or
bladder-like cells. The flowers range from white or yellow to pale pink. The fruit capsules contain
numerous very small kidney-shaped seeds, brown to black in color.
The genus is distributed in the arid southwestern parts of South Africa, including parts of three
provinces: Northern Cape Province, Western Cape Province, and Eastern Cape Province. The plant
populations and individual plants are typically widely scattered, but in the Kougoedvlakte (literally
translated as “Chewing Stuff Plains”) of Namaqualand in the Northern Cape Province, and in the
Kannaland district (literally, “The Land of Kanna”) in the Western Cape Province, the plants were
once locally abundant and traded widely.
Klak et al. (2007) proposed a single genus, Mesembryanthemum, that includes members of the
genus Sceletium. However, for the purpose of this paper, the use of the genus Sceletium is retained,
and the genus Mesembryanthemum (sometimes spelled Mesembrianthemum in former times) is
used when quoting historical texts.
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The taxonomy of Sceletium is complex, and will hopefully become clearer when species based on
standard plant morphological features can be interpreted in the light of DNA-bar coding and plant
chemistry. Eight Sceletium species are recognized in the revision by Gerbaulet (1996):
Sceletium tortuosum (L.) N.E. Br.
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 strictum L. Bolus
Sceletium varians (Haw.) Gerbaulet.
To illustrate the taxonomic complexity at the species level, the following synonyms have been
used for Sceletium tortuosum (L.) N.E.: (Nortje, 2011).
Mesembryanthemum aridum Moench
Mesembryanthemum concavum Haw.
Mesembryanthemum tortuosum L.
Pentacoilanthus tortuosus (L.) Rappa and Camorrone
Phyobolus tortuosus (L.)Bittrich
Sceletium boreale L. Bolus
Sceletium compactum L. Bolus
Sceletium concavum (Haw.) Schwantes
Sceletium framesii L. Bolus
Sceletium gracile L. Bolus
Sceletium joubertii L. Bolus
Sceletium namaquense L. Bolus var. namaquense
Sceletium namaquense L. Bolus var. subglobosum L. Bolus
Sceletium ovatum L. Bolus
Sceletium tugweiae L. Bolus
Part I
historical reports, 1610 - 1971
Early visitors to the Cape of Good Hope in the 17th century frequently emphasized the value
attached to kanna. The captains of trading ships en route to the East Indies thought of the roots of
kanna as a Cape ginseng, and also called it ningin root or ningimm root, a corruption of vernacular
names used for the ginseng root they had seen in Japan and China. Ships of the East India Company,
stopping off at the Cape en route to Japan to stock up on fresh water, fruit and vegetables, were in-
structed to search for the roots as a valued item for trade.
1610
The English East Indiaman e Globe, under the command of Captain Hippon, stopped to re-
plenish water supplies at the Cape of Good Hope en route to the East Indies. Captain Hippon’s lieu-
tenant, Peter Floris, reported:
Being by Gods grace here arrived, wee presently fell to the ordering of the shippe, and
hooping of our caske to fill freshe water, for much refreshing was not here to bee had
att this tyme of the yeare, by the greate quantitie of rayne, being now in the chief-
este of winter so that the mountains laye covered with snowe : during which tyme wee
used great diligence in seeking of the roote Ningimm according to our instruction, the
aforesaid 2 Holland shipps being expressly come thether for the same purpose, being
one of Japan that first discovered the secret; butt, being winter tyme, there was for
this tyme no more to bee done but to go awaye as wyse as wee came, for the olde roote
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being decayed and rotten, the new leaf began onely to come foorth, so that had it not
bene by reason of some information that was gotten of one who here shalbee nameles
for dyvers considerations sake, wee shoulde have bene fayne to have departed without
notice thereof, the right time of gathering the same being in December, January, and
February, being called by the inhabitants Canna. (Moreland, 1934)
1615
Purchas 1625: Saldanha Bay, approximately 130 kilometers north of the Cape of Good Hope: “The
Countrey people brought vs downe of the Root Ningin, whereof wee bought one handful for a piece
of Copper an inch and halfe broad, and two inches and halfe in length. Our men got [some], but not
[so] full, nor ripe, this being not the [season], which in the full perfection is as tender and [sweet] as
[anise seeds]. On the twentieth wee [set sail].” “Ningin, a medicinable root much prized in Japan” .
1660
“It was the control over fields of canna that made the Inqua king Hijkon “chief lord of all kings
and potentates”, for he was one of the patrons whose power flowed from the precious canna that
grew in the desert” (Gordon, 1996, quoting from Jan van Riebeeck’s journal, 2l-22 Sep. 1660, from the
Archives of the Nederlandsche Oost-Indische Compagnie).
1662
In 1652, the Vereenigde Oost-Indische Compagnie or VOC (the Dutch East India Company),
founded a refreshment and recuperation station at the Cape of Good Hope for the benefit of the
crews of its fleets trading between Europe and Asia. The station was to supply fresh fruit and veg-
etables, meat and clean water to the VOC ships whose crews were decimated by scurvy during the
long ocean voyages. In 1662, the first commander of this station, Jan van Riebeeck, received kanna
and sheep from the indigenous people in exchange for gifts, and pronounced that kanna is similar
to Chinese ginseng (Smith, 1966).
1685
dutch expedition to namaqualand (gericke, 2014)
In 1657, the first commander of the VOC’s refreshment station at the Cape, Jan van Riebeeck,
heard from an indigenous interpreter that the copper in indigenous tribal earrings and beads came
from the Namaqua, a tribe of pastoralists who lived to the north of the Cape. Between 1659 and 1663,
seven expeditions were dispatched north to the land of the Namaquas to look for copper and any
other riches, but they all failed, unable to penetrate through the mountainous and difficult terrain.
In 1679, Simon van der Stel was appointed commander of the settlement at the Cape of Good Hope
by the VOC, and concerned himself with the development of agriculture and viticulture and the
improvement of the company’s botanical and herbal garden. In April 1682, some Namaqua people
visited the VOC fort at Table Bay with pieces of good quality copper ore. Expeditions sent north to
find the source of the copper ore failed, unable to cross the mountainous terrain.
In 1685, Hendrik van Rheede tot Drakenstein, a VOC commissioner, arrived at the Cape and gave
Commander van der Stel permission to personally lead an expedition to find the Copper Mountains.
In addition to the search for copper, the expedition was charged with cultivating friendly relations
with the Namaquas, describing the country, and documenting useful plants. The expedition, which
left the Cape of Good Hope on 25 August 1685, was a major undertaking. The party included van der
Stel as commander, his three slaves, fifty-six people of mainly European extraction, a prince from
Makassar (now within Indonesia), forty-six local people of mixed ancestry as drivers and leaders
for the wagon train and accompanying stock animals, and a number of Khoikhoi translators. The
expedition included a carriage, seven wagons, eight carts, a boat for river crossings, and two small
cannon. Technical specialists accompanying the expedition included a navigator, a mineralogist,
and the apothecary and artist Heinrich Claudius, who also served as the expedition’s cartographer.
Claudius had been sent to the Cape from Batavia in the East Indies to collect botanical specimens
for a private collector, and was then retained at the Cape by the VOC on account of his exceptional
abilities as naturalist and artist.
It is not known what became of the original journal of the 1685 expedition, or of Claudius’ origi-
nal drawings, but copies of excerpts from the expedition journal and accompanying drawings were
made shortly after the expedition. One of the copies of the journal is in the collection of Trinity
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College Library, Trinity College MS. 984 (TCMS), and is thought to have been removed from the
Archives of the Dutch East India Company in 1691 or 1692. TCMS includes seventy-one pages of co-
loured drawings believed to be the work of Heinrich Claudius, with descriptive text on alternate
folios. The drawings include two landscapes within the Copper Mountains, a Namaqua man and
woman, forty-three plants, eleven birds, nine reptiles, one fish and eight insects. Watercolor copies
of Claudius’ drawings are in the collection of the Iziko South African Museum in Cape Town, known
as the Codex Witsenii (CW). These copies were made in 1692 for Nicolaas Witsen, a prominent citi-
zen of Amsterdam and a director of the Amsterdam Chamber of the VOC. A third manuscript on the
expedition, written by Jan Commelin (JCMS) about 1687, is held by the Staatsbibliothek Kuturbesitz,
Berlin, as ms. germ. qu. 238.
The journal entry in TCMS, which accompanies a fine painting easily recognized as Sceletium
and including the flower and skeletonized lower leaves, states:
This plant is found with the Namaquaas and then only on some of their mountains.
It is gathered in October and is called Canna. It is held by them and the surrounding
tribes in as great esteem as the betel or areca with the Indians. They chew the stem as
well as the roots, mostly all day, and become intoxicated by it, so that on account of
this effect and its fragrance and hearty taste one can expect some profit from its culti-
vation. Found on the 20th October. (Waterhouse et al., 1979)
The journal entry in Codex Witsenii, accompanying a copy of the painting of Sceletium, states:
This is from the Namaquas and also other nations the famous kanna, which they carry
in the mouth daily and chew, as the Indians do with Areca, and who do it often can eas-
ily get drunk from it, it is held in great esteem by them, like all things that corrupt the
mind, and make drunk. And that there is something particular in these plants is seen
not only from the activity, but also the pleasant and cordial taste, are found nowhere
but on certain mountains in the country of the Namaqua and collected in October;
found 20 October 1685.
1686
Guy Tachard (1651–1712), also known as Père Tachard, was a French Jesuit missionary and math-
ematician of the 17th century who was sent on two occasions to the Kingdom of Siam by Louis XIV,
and en route spent time at the Cape of Good Hope. Translated from the original French,
This captain, pleased with his gifts, sent us in gratitude two fat tail sheep, each tail
weighing more than twenty pounds, with a large vessel full of milk, and a certain herb
which they call Kanna, it is apparently this famous plant that the Chinese call Ginseng;
for Monsieur Claudius, who has seen it in China, asserts that he had found two plants
at the Cape, and shows us the whole figure which he had painted in nature.” (Tachard,
1686)
1726
François Valentijn was a Dutch minister, naturalist and author. In his Beschryvinge van de Kaap
der Goede (Descriptions of the Cape of Good Hope), he noted that the “Canna of the Hottentots
closely resembles the Chinese root Nisi or Ginseng” (Serton, 1971).
1731
Peter Kolben was sent to the Cape of Good Hope with letters of introduction from the mayor of
Amsterdam, with a mandate to compile a comprehensive description of South Africa for geo-
graphical research and surveying. He wrote detailed accounts of the geography, climate, flora and
fauna, followed by a study of the indigenous Khoi people (called Hottentots at that time), covering
their language, religion, lifestyle and customs:
There is a Root, gather’d in the Hottentot Countries, called Kanna; which is in [such Es-
teem] among the Hottentots for its great vertues that they almost adore it. What greatly
enflames the Value of this Root, is its Scarcity; for ‘tis very rarely found. They look upon
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it as the [greatest] Chearer of the Spirits, and the [noblest] Restorative in the world.
They will give [almost] any Thing in Exchange for it; and will, any of ‘em, run Twenty
Miles upon an Errand, or perform a hard Day’s Work, for a very small Bit of it. With
a piece of Kanna you may manage ‘em [almost] in any Manner you [please]. You win
their hearts Forever by [presenting] them with the smallest Chip of it; and they will
run, fetch and carry for you like your Slaves, under [so] charming an Obligation…I have
often [seen] the Effects of Kanna upon Hottentots. They chew and retain it a [consider-
able] Time in their Mouths. But taking generally too much of it at a Time, it drowns ‘em
in Intoxications. They chew it not long, before their Spirits [visibly] [rise], their Eyes
brighten, their Faces take a jovial Air, and they [Sport] and wanton under a [thousand]
Gaieties of Imagination. But in the End it [Strips] ‘em of their [Senses], and throws ‘em
into the [wildest] Deliria (Kolben, 1731).
1763
De la Caille (1763): “The Canna of the Hottentots is entirely different from [Ginseng]. I have seen
both, they are entirely different. They harvest the root in the months of November and December,
add water and put some honey in it, and leave it in the rocks to ferment. They drink it while it lasts,
abruptly unable to do anything. When the supply is exhausted, they are long sick; eating orca re-
stores them.”
1772-1775
Carl Peter Thunberg was a Swedish botanist and physician who had been a student of Linnaeus.
He made two journeys to the Eastern Cape region of South Africa between 1772 and 1774, and report-
ed that valuable narcotic plants were found in the vicinity of the present-day town of Oudtshoorn in
the Little Karoo, in an area formerly occupied by the Attaqua Khoikhoi. This area of South Africa is
still known as Kannaland. According to Thunberg (Forbes, 1986),
Kon, was a name given by the Hottentots to a shrub that grew here (Mesembryanthe-
mum 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 it be chewed im-
mediately 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 hawk it about, frequently
to a great distance, and exchange it for cattle and other commodities.”
1851
The Great London Exhibition of 1851 may have been a pivotal moment in the history of Scele-
tium, where the plant was exposed to international visitors that would have included physicians,
chemists and pharmacists. A collection of the most important Cape botanical medicines was sent to
the exhibition from Cape Town by Messrs S.H. Scheuble & Co. (Gunn and Codd, 1981). Karl Wilhelm
Ludwig Pappe, a German-born physician and botanist who moved to Cape Town to practice as a
physician, wrote a small book as a commentary to accompany the exhibited medicinal plants. In
the entry for Sceletium tortuosum (as Mesembryanthemum tortuosum. Lin.), Pappe wrote, “This species,
a native of the Karroo, appears to possess narcotic properties. The Hottentots, who know it by the
name Kauw-goed, are in the habit of chewing it, and become intoxicated, while the farmers use it in
the form of decoction or tincture, as a good sedative” (Pappe, 1868).
1856
Confusion between kanna and ginseng seems to have persisted well into the 19th century, with a
French-English Dictionary of the time describing kanna as a species of ginseng (Collot, 1856).
1858
The distinction between processed and unprocessed plant material, and differences in the activ-
ity of different Sceletium species, is made by Tully: “Mesembryanthemum emarcidum, like Nicotiana
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Nigel Gericke
tobacum, is not narcotic until it has undergone a certain change in consequence of it being treated in
a peculiar manner. Mesembryanthemum tortuosum is considered narcotic without any such change”
(Tully, 1858).
1873
The Bleek and Lloyd Archive of the University of Cape Town is a remarkable collection of /Xam
San oral literature, language and ethnography documented in Cape Town by W. H. I. Bleek and Lucy
C. Lloyd between 1870 and the early 1880s. They became aware of a group of /Xam San prisoners at
the Breakwater Convict Station in Cape Town and received permission for //Kabbo to stay in their
Mowbray home as a research participant. Later, other San prisoners were also allowed to stay in the
house, including ≠Kasiŋ. //Kabbo, meaning “Dream”, stayed with Bleek and Lloyd between February
1871 and October 1873. He was sent from the Breakwater Convict Station, where he had been impris-
oned for two years for stock theft or sharing in the spoils of theft, as prisoner Number 4628. ≠Kasiŋ
arrived at Bleek and Lloyd for the first time from November 1873 until March 1874, after //Kabbo had
left. He had been imprisoned at the Breakwater Convict Station for culpable homicide and served
four years of a five-year sentence as prisoner Number 4435 (Digital Bleek & Lloyd, 2017).
//Kabbo and ≠Kasiŋ were shown a number of “Bushman medicines” that had been found in the
hut of a “Bushman sorcerer”, and their comments on these medicinal plants were transcribed into
English by Wilhelm Bleek and Lucy Lloyd (MSS BC151 006; Prader-Samper, 2007). I was surprised
to find that none of the botanical names of these plant medicines was known. Two informants, //
Kabo and ≠Kasin independently identified the same plant sample as kaauwgoed, and on this basis
the botanical identity was established as Sceletium sp. since no other South African plant has before
or since been given this Dutch vernacular name. Indeed, the Afrikaans name for Sceletium to this
day is kougoed, derived from the older Dutch kaauwgoed, meaning “chewing stuff.” We finally have
the first reports on the uses of Sceletium from indigenous people, in their own words, as well as the
original /Xam San name for the plant as !k”wa:ï or !k”wai:n.
Bleek’s notes documented from //Kabbo !k”wa:ï singular and plural. Kaauwgoed
A small plant found on the great mountains growing out of crevices in the rocks. It is
chewed by Bushmen, and gives strength to their limbs; and takes away pain and makes
their memory strong. The two Bushmen from Stuurmansfontein had some with them
to enable them to walk till they met the wagon. Is found around the Berg Bushmen.
Lloyd’s notes documented from ≠Kasiŋ !k”wai:n Kaauwgoed
If a little child that is still being suckled is ill inside, they take a little piece of it, & put it
into a spoon of cold water, & rub it about in it, the water becomes yellow (like tobacco
water), and they give it to the child to drink. Men and women chew it; and swallow
their saliva. The plant is in some cases short, but in others long, like a pumpkin in
growth. It grows on the ground. It grows in ≠Kasiŋ’s place.
1874
The botanical identity of a sample of kougoed was confirmed to be Mesembryanthemum tortuosum
and the uses of it were described: “The Koegoed [sic], besides being used as stated by Mr. Keyworth
as a sedative for cattle, is chewed by the Hottentots as an intoxicating agent, and appears to possess
narcotic properties which deserve further attention” (Holmes, 1874).
1876
Twenty-five years after the Great London Exhibition, Sceletium may have become available as
a botanical medicine in the United States, evidenced by the inclusion of Mesembryanthemum tortu-
osum in C.E. Hobbs’ Botanical Hand-Book (Hobbs, 1876) and in J.M. Nicholl’s Botanical Ready Reference
(Nicholl, 1895). These books were lists of botanicals apparently in common use in the United States,
and written for apothecaries and pharmacists. In both books, the plant was classified as a narcotic.
1896
The first pharmacological research on Sceletium was reported by Isaac Meiring in the Transac-
tions of the South African Philosophical Society. In this paper, Meiring gives the locality the plant
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material came from, the vernacular name as “Hoentot’s Kauwgoed” and had the plant material used
in his experiments botanically identified as Mesembrianthemum tortuosum L.:
Like so many Cape plants, it has great medicinal virtues ascribed to it, chief of which
are its soporific influence on young children and its curative and quieting effect on
them when suffering from acidity. It is alleged that for these purposes the plant is very
widely used, the method of procedure being one or two drops of the juice of the green
plant is given to the child, who then enjoys a deep, quiet rest for several hours.
Meiring made a crude alkaloid extract from the plant, and noted that when injected into a frog
it had a marked hypnotic effect. He then went on to do some “clinical experiments” with a tincture
of dry plant material, and found it had marked pain-relieving activity “without concomitant bad ef-
fects.” Meiring then gave his remaining plant material to a Dr. Rubenstein to take to Germany, where
a Dr. Fromm in Freiburg found it contained a compound capable of being crystallised, and which
resembled morphine in its action (Meiring, 1896).
1898
In his book Die Heilpflanzen Der Verschiedenen Völker Und Zeiten11 , Dragendorff lists two
species of Sceletium: “Mesembryanthemum anatomicum Hav. (Mesembryanthemum emarcidum Thbg).
Herb is used as a light narcotic (and smoked). Also Mesembryanthemum tortuosum L.” (Dragendorff,
1898). 1905
Juritz stated that Mesembryantheum tortuosum is soporific, causes dilatation of the pupil, and
decreases sensation (Juritz, 1905).
1913
Zwicky isolated a crude alkaloid extract from Mesembryanthemum tortuosum, which he called
mesembrine, and on testing with various chemical reagents concluded that there was no similarity be-
tween cocaine and mesembrine; he further concluded that this active principle, mesembrine, was also
found in Mesembryanthemum expansum. In the first detailed documentation on self-ingestion of Sce-
letium plant material and alkaloid extract, Zwicky reported the following observations (Zwicky, 1913):
I. After chewing 5g of Sceletium:
The taste was bitter, astringent, unpleasant, irritating to the mouth. During the chew-
ing, tingling was noticed on his tongue, later weak anaesthesia in the mouth, which
lasted for some time. The pulse remained normal, while the temperature was weakly
increased from 36.9 ° to 37.1 °. I noticed nausea, headache, loss of appetite.
II. After taking a decoction of 15g of Sceletium at 14:00:
Half an hour after taking the decoction I felt blood pressure in the head and slight
headache, but it did not last long. I had the feeling that the food was not digested and
only at 10:30 in the evening appetite returned. In general, the effects were not very dif-
ferent from the 1st experiment. ; in any case, they were not 3 times as strong as the first.
III. After taking 0.15g of an alkaloid concentrate extracted from Sceletium at 15:00:
Congestion of the head, noises in the ears, tiredness accompanied by slight tremors in
the arms and legs, headache, general depression; loss of appetite until 10 in the evening.
1928
The Khoikhoi chew the leaf for the relief of toothache and pain in the abdomen, “the effect ap-
parently being narcotic” (Laidler, 1928).
1 Rough translation: e Medicinal Plants of Dierent Peoples and Times.
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1937
Crystalline pure alkaloid was isolated from Sceletium plant material obtained from Namaqual-
and (Rimington and Roets, 1937), identified as mesembrine, and assigned the formula C17H23O3N.
It was concluded that this formula is identical to hyocyamine and atropine, suggesting that mesem-
brine is a tropane alkaloid. 1960
All Sceletium species “contain the poisonous principle “mesembrine” a relative of cocaine and
other principles” (Jacobsen, 1960). Jacobsen noted that kougoed was still being made traditionally
and sold, and concluded “perhaps it may give a valuable medicine.”
1962
Sceletium tortuosum “is used as a narcotic by the African in the Queenstown district” (Watt &
Breyer-Brandwijk, 1962). A geologist and mining engineer observed that “the Nama have a universal
addiction to kougoed”, and it “is also used by the Nama for the relief of all types of pain, and to relieve
hunger…A Nama mother chews the root and ejects her saliva into the mouth of her child from an
early age” (Watt & Breyer-Brandwijk, 1962).
1971
Herre (1971) stated that while other members of the Aizioaceae also contain mesembrine, it is
present in lower concentrations than in Sceletium, which produces mesembrine when grown in
North Carolina, but not in Europe and northern countries. He noted that the German pharmaceuti-
cal company C.F. Boehringer & Söhne of Mannheim was investigating Sceletium, and also the com-
pany S.B. Penick in New York.
Table 1. Summary of historical reports on preparation and uses of Sceletium species
SUBJECT NOTES REFERENCES
Species Mesembryanthemum tortuosum Tully, 1858; Pappe, 1868 ; Hobbs, 1876; Nicholl,
1895 ; Meiring, 1896; Juritz, 1905; Zwicky, 1913;
Tully, 1858;
Mesembryanthemum emarcidum Forbes, 1986; Holmes, 1874
Mesembryanthemum anatomicum Dragendorff, 1898
Mesembryanthemum expansum Zwicky, 1913
Folk names Ningin, Ningimm Purchas 1625; Moreland, 1934
Kanna, Canna Tachard, 1686; Kolben, 1731; Moreland, 1934;
Serton, 1971; Smith, 1966; Wilson, 2002; Forbes,
1986
Kauw-goed; Kaauwgoed; Kauwgoed;
Koegoed, kougoed
Holmes, 1874; Meiring, 1896; Marloth, 1917;
Smith, 1966; Forbes, 1986
!k”wa:ï ; !k”wai:n Prader-Samper, 2007
Preparation Roots fermented with honey
Whole plant fermented
Tincture
Cold water infusion
Drops of freshly squeezed plant
Smoked
Roots chewed, saliva given to infant
De La Caille, 1763
Forbes, 1986
Pappe, 1868
Prader-Samper, 2007
Meiring, 1896
Forbes, 1986; Dragendorff, 1898
Watt & Breyer-Brandwijk, 1962
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Nigel Gericke
SUBJECT NOTES REFERENCES
Activities Intoxicant
Narcotic, Sedative, Hypnotic
Decrease sensation, local anaesthesia
Nausea, loss of appetite, decrease
hunger
Toothache
Elevate mood
Analgesic
Pain
Endurance
Memory
Waterhouse et al, 1979; Kolben, 1731; Tully, 1858;
Pappe, 1868; Holmes, 1874
Kolben, 1731; Tully, 1858; Pappe, 1868; Holmes,
1874; Hobbs, 1876; Nicholl, 1895; Meiring, 1896;
Dragendorff, 1898; Juritz, 1905; Laidler, 1928;
Watt & Breyer-Brandwijk, 1962
Juritz, 1905; Zwicky, 1913; Watt & Breyer-Brand-
wijk, 1962
Zwicky, 1913; Laidler, 1928
Laidler, 1928
Kolben, 1731
Meiring, 1896; Laidler, 1928; Watt & Brey-
er-Brandwijk, 1962
Prader-Samper, 2007; Laidler, 1928
Prader-Samper, 2007
Prader-Samper, 2007
Part II
ethnobotany, ethnopharmacology
& pre-clinical research 1995-2017
ethnobotany
In late 1991, I was given a sample of kanna by the ethnobotanist Fiona Archer, who had been doc-
umenting local plant uses in Namaqualand for an MSc degree in anthropology at University of Cape
Town. At the time, I was searching for South African plants with psychedelic activity. On inquir-
ing if she had encountered possible psychoactive plants from Namaqualand, Fiona told me about
a plant called kougoed, traditionally used by locals, and that when she had tried some it felt as if her
perceptions of time and space had been altered. Fiona gave me a brown paper bag containing about
500g of stringy, brown, traditionally fermented and dried Sceletium. I chewed a few grams of the
plant material, and after about fifteen minutes, the plant caused a rather sudden rush of euphoria.
Over the following hour, this gradually changed to a feeling of deep calm that persisted for some
four or five hours. Following from this intriguing initial experience, my wife Olga, myself and Fiona
began a period of self-experimentation and gave samples of kanna to friends, fellow doctors and
psychiatrists, anthropologists, botanists and an African traditional healer. I wrote up some of this
early experimentation in Smith et al., 1996:
Additional information on the effect of kougoed has been documented from a dozen
individuals who self-experimented with the traditionally prepared plant material, and
provided oral anecdotes of these experiences. Most users found that kougoed induced
a marked anxiolytic effect. One informant used about 5ml of powdered kougoed orally
before giving a lecture he was anxious about. He reported feeling relaxed throughout
the lecture with no cognitive impairment. Many users felt that kougoed, on its own or
with alcohol, enhanced social intercourse at parties and functions. Users felt consider-
ably less inhibited and self-conscious, and more open than usual in conversation with
strangers. One user claimed she felt that kougoed was a “truth drug”. Of kougoed, some
claimed there was a synergistic effect with alcohol, and with smoked dagga (Cannabis
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Nigel Gericke
sativa). One experimenter, a polysubstance abuser, used kougoed in addition to alcohol
(whiskey) and smoked dagga. He experienced a traumatic flashback to a violent event
he had participated in during a regional armed conflict.
A polysubstance abuser, addicted to nicotine and a frequent abuser of alcohol and dag-
ga, reported that after a single dose of kougoed he felt no craving for alcohol, dagga or
nicotine for 4 days. Some reported euphoria as well as a feeling of meditative tranquil-
ity. Several users felt that the relaxation induced by kougoed enabled one to focus on
inner thoughts and feelings, if one wished, or to concentrate on the beauty of Nature.
Some informants reported heightened sensation of skin to fine touch, as well as sexual
arousal. A senior traditional healer, not previously exposed to kougoed, tried it and an-
nounced that it “relaxes the mind” and makes one’s body feel “light” the following day.
From 1995 to 1999, I undertook detailed ethnobotanical studies on Sceletium in the field to docu-
ment the local uses of the plant, and to determine whether the plant had addictive potential. The fo-
cus of this field work was in the rural hamlets of Paulshoek and Nourivier in the Kamiesberg moun-
tains of Namaqualand, not far from the 1685 trail of the Dutch expedition led by Simon van der Stel.
Fieldwork was also undertaken in the vicinity of Kougoedvlakte (the area named after the once-abun-
dant wild Sceletium tortuosum resource of this arid plain), and interviews and discussions were held
with shepherds and goatherds in the western area of what is now the Riemvasmaak Community
Conservancy. In rural hamlets, elderly male and female members of the local community, who had
themselves used Sceletium for many decades, were interviewed. Three key informants, recognized by
the communities for their specialist knowledge on medicinal plants, were selected for more detailed
interviews: the renowned traditional healer Gert Dirkse or “Oom Gert” (meaning Uncle Gert) living
near Paulshoek; a younger healer, Jap-Jap Klaase, living in Nourivier; and the shepherd Lodewyk
Mories, living near the farm Ratelkraal situated between the towns Springbok and Pofadder.
Some of this ethnobotanical research has been published in Smith et al., 1996, Gericke & van
Wyk, 2000, and in Gericke & Viljoen, 2008. Sceletium tortuosum is typically harvested by local people
during the dry-season months from October through to January, when the plants have partly died
back and become yellowish in colour. The plants are often found growing under woody shrubs, par-
tially shaded and sheltered from the wind and from foraging by animals. The died-back yellowing
plants are regarded as having more “power” than the vigorously growing green plants of the June to
August winter rainy season. The plant is cut above the ground, leaving the roots and a small portion of
stem behind to resprout. While some collectors gather the entire uprooted plant, older healers claim
this is not following tradition and will prevent the plants from regenerating. The collected succulent
plant material is crushed with a large stone on a flat rock and the resulting dripping wet fibrous pulp is
put into a plastic bag. According to local people, traditional sheepskin bags were used in former times.
The plastic bag is tied to exclude air, and the material is allowed to macerate in the hot sun for eight
days with intermittent mixing. On the eighth or ninth day, the plant material is spread on a flat rock to
dry in the sun, resulting in dry clumps of amorphous, light brown plant material with a characteristic
musty “old socks” smell. This is the traditional kougoed or kanna of the Namaqualanders.
addiction potential
The following excerpt is taken verbatim from a field report (Gericke, 1995). In order to assess the
potential for addiction, I had asked my friend Dr. Greg McCarthy, an academic addictionologist, to
accompany me on a field trip to Namaqualand and give me an independent opinion on this. Sadly,
Greg passed away in 2016, still working as an academic psychiatrist and addictionologist.
“In order to assess whether Sceletium use leads to addiction or dependence, a consultant psychi-
atrist from the Cape Town Drug Rehabilitation Centre, Dr. Greg McCarthy, accompanied Dr. Gericke
on a field trip to Namaqualand to investigate the use of kougoed by traditional healers and members
of rural communities. Dr. McCarthy is a consultant psychiatrist at Valkenberg Hospital Community
Service, and was recently a consultant at Avalon, an alcohol treatment centre. He serves on the West-
ern Cape Alcohol and Drug Forum.
“The DSM-IV criteria for dependence were translated into a questionnaire appropriate to the
rural population. Three well-respected traditional healers, and eight long-term regular users of kou-
goed were interviewed. All were cooperative and open. There was clear convergence of the anecdotes
and all denied any hallucinogenic or psychotomimetic effects of kougoed.
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Nigel Gericke
“While kougoed is used as a euphoriant or intoxicant, almost solely by elderly men, its medicinal
qualities are highly regarded by the entire community. The recognized medicinal uses include use
as an hypnotic or sedative, as a mild laxative, as a gripe-water, for abdominal cramps, and for alco-
hol rehabilitation. All research participants were adamant that kougoed was less habit-forming than
alcohol, tobacco or dagga [Cannabis sativa].
“Tolerance was denied by all users except one, who reported “jy raak gewoond daaraan” [“you get
used to it”]. It was not clear whether he was referring to true tolerance, where increasing doses are
required to bring about the same effect, or whether he was referring to the fact that one gets accus-
tomed to the use of kougoed, as the naïve user can experience nausea.
“Withdrawal signs or symptoms were not reported by anyone. This significant finding is reli-
able, because even regular users run out of supplies of kougoed due to decreased availability of the
material. Mr. Mories (pers. comm.) reported there were no signs or symptoms of withdrawal even
if a person ran out of kougoed after six months of habitual use. Some regular users would perhaps
have a slight feeling as if something was missing, and some would make an effort to contact friends
who may have some kougoed, but would not run into any difficulties if no more was obtained. All
confirmed it would be far easier to give up kougoed than alcohol, tobacco or dagga [ Cannabis sativa].
“An idea of the social and occupational functioning of the informants was easy to gauge al-
though formal employment is scarce. The local environment is harsh, and daily living requires hard
work, including walking long distances to collect brushwood for firewood, shepherding sheep and
goats, and ploughing wheat-fields using donkey-drawn ploughs. There were no reports of “social
dropouts” from habitual kougoed use, and use in this rural context can be viewed as a socially sanc-
tioned activity. It is not possible to extrapolate what effect habitual use of kougoed as an euphoriant
would have outside of this context.
“The medicinal use of kougoed, administered for specific indications, in lower doses, taken less
frequently and for a finite duration must be seen as entirely separate from use as an euphoriant.”
(Gericke, 1995).
well-being
Kanna was commonly used by elderly men and women for a sense of calm and well-being. Elder-
ly research participants, some in their eighth and ninth decade of life, were interviewed who had
chewed quids of kanna daily throughout their adult lives. A small quid of fermented Sceletium is
kept in the cheek and sucked, and the resulting saliva is swallowed. For a sense of calm and well-be-
ing, the quid is removed about fifteen minutes later. Men in the community then place the wet quid
in their hatband to dry out so it can be sucked on or chewed later, a sequence repeated a number of
times during the day. The author was cautioned “Doktor, jy moet leer hoe om dit te gebruik” – “Doctor,
you must learn how to use it” – because once one begins feeling intoxicated by it, one has already
chewed far too much. The intention of these users is to enjoy a pleasant sense of well-being, not to
get intoxicated.
intoxication
There were convergent reports that some people, invariably older males rather than females, did
indeed use kanna on occasion as an intoxicant or euphoriant. No visual or auditory hallucinations
were associated with the intoxication, and the state was described as being similar to being intox-
icated with alcohol: “dis onse droë drank” – “it is our dry liquor” (Lodwewyk Mories, pers. comm.,
1995). Plants from particular areas are regarded as being more potent intoxicants, and through the
traditional “fermenting” process, the kanna would give a better “trek” – euphoria or a high. Younger
men in the community were not using kanna at this time, and it seemed the use of tobacco, alcohol
and possibly also dagga (marijuana) had displaced the former use of kanna by younger people in
these rural communities.
insomnia
Kanna is used as a hypnotic, with a small quid kept in the cheek by some users when going to
bed. Paradoxically, some participants reported that if too much kanna was used, it would in fact
cause insomnia.
alcoholism
Both of the healers, Gert Dirkse and Jap-Jap Klaase, maintained that kanna was used to wean alco-
holics off of alcohol, but only if the alcoholic was committed to stop drinking. Alcohol was replaced
133
Nigel Gericke
Gert Dirkse with Dr. Nigel Gericke, Paulshoek, Namaqualand, 1995.
The late Gert Dirkse, right, the last great healer of the Kamiesberg Mountains, with Sceletium tortuosum, and
Jap-Jap Klaase, left.
134
Nigel Gericke
by the chewing of kanna, and it was not considered to be a problem for the person to subsequently
stop using the kanna. In some cases, a strong decoction of kanna would be added to a bottle of wine,
so that if the alcoholic drank this wine it would cause vomiting and an aversion to wine.
consciousness
The healer Gert Dirkse maintained that using kanna “opened the mind”, and he used both hands
expanding out from his temples to demonstrate this (pers. comm., 1999). He denied that the plant
could cause any visions.
pregnancy
A quid of kanna is commonly chewed by women during pregnancy for treating nausea, indi-
gestion, or for treating constipation in pregnancy. It was noted that if one took too much it had a
sedating effect. The plant was not known to cause abortion or congenital defects.
parturition
Infusions of kanna are taken to help expel any remaining afterbirth, to help contract the uterus,
for abdominal pain after giving birth and for indigestion.
infants
Kanna is commonly administered to infants to treat colic, excessive crying and stomach cramps.
A small amount of dried herb (the samples demonstrated were estimated to be ~200-500 mg) or
fermented dried herb is wrapped in cloth and dipped in breast milk in a teaspoon until the liquid
has turned slightly brown. A few drops of this liquid are given orally to make the infant sleep rest-
fully. Dried fermented herb is also lightly fried in sheep fat taken from the tail of a fat-tail sheep;
this is strained through a cloth and kept in a small bottle. One to two drops of this medicated liquid
fat are given to an infant with colic. The baby usually falls asleep soon after the administration of
the drops. None of the mothers had ever heard of an infant needing to be taken to a doctor after too
much kanna had been administered; they acknowledged that sometimes too high a dose is inadver-
tently given, but all that happens is that the baby will sleep for some hours.
children
Hot-water infusions or decoctions of kanna are given to children for constipation, abdominal
pain, winds and also as a “kalmeermiddel” or calming medicine. A child suffering from abdominal
pain will fall asleep soon after the kanna is administered.
other
Kanna i s als o use d in Namaqualand to treat asthma, abdominal cramps, constipation and headache.
raw material supply
Elderly Namaqualanders confirmed that kanna had once been plentiful, but was now very scarce
as it had been overharvested for sale to local trading stores and shops in the local towns, including
the town of Springbok. Lodewyk Mories (pers. comm., 1995) recalled a time when as a young boy in
the 1940s, he had seen wagonloads of kanna being transported from Namaqualand, presumably des-
tined for Cape Town. Some local farmers maintained that wild stocks of Sceletium had been eaten
by overgrazing sheep; however, indigenous shepherds with more intimate knowledge of the eating
habits of stock maintained that sheep would only nibble on Sceletium and then move on, and that it
was not the sheep that had depleted wild stocks of Sceletium, but people who had overharvested the
plant, who had “run after the money.”
It was clear that for the development of a product (at that time, for the South African phar-
maceutical company Pharmacare Limited, as I was the Phytomedicines Development Manager),
wild-harvesting of plants would not be ecologically sustainable, and that selections of Sceletium
would need to be cultivated from scratch as a new crop. For this purpose, plant chemotype studies
were started by Professor Ben-Erik van Wyk, and plant propagation and production studies were
started by the late Professor Earle Graven and Myke Scott of Grassroots Natural Products. This work
was on contract to Pharmacare Ltd., and directed by myself. From 1999 onward, the propagation and
production of Sceletium work was continued by Du Roi Nurseries, and in 2004 by Niche Botanicals
135
Nigel Gericke
(Pty) Ltd., in cooperation with Hannes de Lange, PhD. The first successful large-scale commercial
production of a select chemotype of Sceletium tortuosum, both under shade-house conditions and
open-field conditions, was achieved in 2008 by Du Roi Nurseries and H.L. Hall and Sons Ltd., grow-
ing the plants on contract to the South African company HG&H Pharmaceuticals (Pty) Ltd. It had
taken more than a decade of investment in research into plant selection, propagation and produc-
tion studies to demonstrate that Sceletium could be grown successfully on a large scale as a new
commercial South African crop. The reliable supply of raw material with a defined alkaloid content
and composition finally allowed the development of a standardized and characterized spray-dried
extract of the plant, suitable for all subsequent pre-clinical and clinical research.
chemistry
The literature on the Sceletium alkaloids has recently been thoroughly reviewed (Krstenansky,
2017), and validated analytical methods have been described for quantifying the major mesem-
brine-type alkaloids including mesembrine, mesembrenol, mesembrenone, mesembranol,
Δ7mesembrenone, and epimesembranol (Patnala & Kanfer, 2010; Shikanga et al., 2012).
Based on the alkaloid skeleton, Jeffs et al. (1982) separate Sceletium alkaloids into four structural
groups:
I the 3aaryl-cis-octahydroindole class (e.g., mesembrine)
II the C-seco mesembrine alkaloids (e.g., joubertiamine)
III alkaloids containing a 2,3-disubstituted pyridine moiety and two nitrogen atoms (e.g., Sce-
letium alkaloid A4)
IV a ring C-seco Sceletium alkaloid A4 group (e.g., tortuosamine).
The revision of Gerbaulet (1996) recognizes eight species of Sceletium, of which the alkaloids
in Sceletium strictum, Sceletium subvelutum (=Sceletium varians), Sceletium tortuosum, Sceletium jouber-
tii and Sceletium namaquense have been studied in great detail. The latter two species are now con-
sidered synonyms of Sceletium tortuosum. The local utilization of Sceletium as kanna, kaauwgoed or
kougoed has included a number of Sceletium species and a wide range of Sceletium alkaloids. Com-
pounds that have been isolated from the genus Sceletium are presented in Fig 5.
extract sceletium tortuosum, zembrin®
The first standardized extract of Sceletium tortuosum was made by the German company Gehrli-
cher GmbH in 1999 on contract to my consulting company, African Natural Health Close Corpora-
tion. The first fully standardized and characterized extract of Sceletium tortuosum, Zembrin®, was
produced to EU-GMP standards by the Spanish company Polifenoles Naturales SL. The company is
now renamed Nektium Pharma SL, and continues to manufacture the extract Zembrin® on contract
to the company I co-founded, HG&H Pharmaceuticals (Pty) Ltd. This extract was developed and
commercialized from a cultivated special selection of plants that are relatively rich in mesembrenol
and mesembrenone as the major compounds, and relatively low in mesembrine and mesembranol.
Zembrin® is standardized to contain 0.4% total alkaloids by weight, with the relative alkaloid com-
position of mesembrenone + mesembrenol ≥60%, mesembrine <20%, and mesembranol must be
present in the UPLC profile. The structures of these four compounds are given in Figure 6.
prior informed consent
benet-sharing agreement
The development of a product from a medicinal plant used by indigenous people has to take
into consideration the contribution that indigenous knowledge – past and present – makes to the
foundational ethnobotanical research that gives a preliminary indication of safety, therapeutic in-
dications, and in the case of Sceletium, the apparent lack of potential for dependence. Local par-
ticipants were able to point out plants that they considered mild in effect in terms of euphoria or
intoxication (called mak or “tame” plants), and plants which they considered a trek variety, which
were considered to me far more potent plants than the mak variety and which could cause euphoria
or intoxication, especially after fermentation.
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Nigel Gericke
Two years before the launch on the South African market of the standardized Sceletium extract
Zembrin®, a prior informed consent benefit-sharing agreement was negotiated and signed between
the South African San Council (SASC) and HG&H Pharmaceuticals (Pty) Ltd. (HG&H). The agree-
ment was signed on 21 February 2008, and must be one of the first such agreements entered into
with indigenous knowledge holders. This agreement was the result of many months of meetings
and discussions with the South African San Council, who were supported in their negotiations by
the internationally recognized human rights attorney Roger Chennels, ensuring that the SASC were
well informed and that the agreement reached by the two parties was aligned with international
best practices.
This benefit-sharing agreement recognized that the San were the primary indigenous knowl-
edge holders of the South African endemic plant Sceletium tortuosum. The SASC in turn recognized
that the original ethnobotanical research conducted by myself in the Namaqualand communities
of Nourivier and Paulshoek contributed important information on the uses of Sceletium. In recogni-
tion of this contribution to the project, the SASC agreed to share 50% of royalty payments made to
SASC with these two communities in an agreement signed on 30 June 2008 (Gericke, 2011). Royalty
payments have been made to the SASC by HG&H from 2008 to the present time, at a rate of 5% of
royalties on all sales of the extract Sceletium tortuosum, Zembrin®, and an additional 1% royalty on
the use of the SASC logo on products containing Zembrin®. The payments are based on total in-
voiced sales, not on “profit” (revenues after costs). The SASC in turn have paid 50% of the royalties
to the two communities of Paulshoek and Nourivier, represented by local community organizations
established for this purpose. All payments are made into a South African Government trust fund
established for this purpose, and are then paid out in full to the SASC, who in turn pay the two Na-
maqualand community groups. This prior informed consent benefit-sharing agreement has been
cited as a positive case study in the commercialization of a product derived from indigenous knowl-
edge (Iatridis and Schroeder, 2016).
pharmacology
serotonin reuptake inhibition (sri)
On 25 July 1989, President George Bush, in response to reports by the National Advisory Council
of the National Institute of Neurological Disorders and Stroke and the National Institute for Mental
Health (NIMH), and the urging of Congress, signed a presidential declaration designating the 1990s
as the Decade of the Brain, a national research endeavor to better understand how the brain and
nervous system is organized, how it functions, why it fails to function and what can be done to pre-
vent and treat dysfunction. As part of this research, NIMH screened large numbers of compounds
through a research agreement with the company Novascreen. In November 1995, I was working as a
Visiting Scholar at the US Pharmacopoeia (USP), and not far from USP was the NIMH. I was intro-
duced to Dr. Linda Brady, who was then the chief of the Neuropharmacology and Drug Discovery
Program. Dr. Brady kindly agreed to screen an extract of Sceletium as well as isolated pure mesem-
brine. Both the extract and mesembrine turned out to be exceedingly potent 5-HT uptake inhibitors
in the radioligand binding screening and in a subsequent functional assay. This work formed the ba-
sis for US Patent 6,288,104 (Gericke and Van Wyk, 1999), which disclosed the use of mesembrine and
related compounds, and extracts of Sceletium standardized to these compounds, as serotonin-up-
take inhibitors (SRIs), and the use of these compounds in pharmaceutical formulations for the man-
agement of depression, anxiety, drug dependence, bulimia and obsessive-compulsive disorder.
Subsequently, the standardized Sceletium extract Zembrin® was confirmed to be an SRI with an
IC50 of 4.3μg/ml, and mesembrine was found to be the most active alkaloid against the 5-HT trans-
porter (SERT), with a Ki of 1.4nM (Harvey et al , 2011). See Table 2 below. In fact, mesembrine is a more
potent inhibitor on SERT than fluoxetine (Prozac).
Phosphodiesterase-4 Inhibition (PDE4 Inhibition)
I self-experimented with isolated pure mesembrine on a number of occasions from 1996 to 1999,
on some occasions with a friend and fellow natural products enthusiast, Dr. George Davidson. Iso-
lated pure mesembrine, taken sublingually in tincture form or on a blotter, resulted in a tangible
entactogenic effect with an onset of action some ten to fifteen minutes after taking 100μg. Higher
doses at about 500μg gave an experience not dissimilar to MDMA but far more tranquil. It was clear
that there had to be additional CNS mechanism/s of action in addition to the SRI activity.
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Nigel Gericke
Cultivated Sceletium for the production of the standardized extract Zembrin®.
Fig. 1 The four alkaloids quantified in the standardized Sceletium extract Zembrin.
Mesembrenol Mesembrenone Mesembrine Mesembranol
Compound
Inhibition of SERT
Ki nM
mesembrenone 27
mesembrine 1.4
mesembrenol 63
Compound
PDE4B Inhibition
IC50 μM
Rolipram 0.13
mesembrenone 0.47
mesembrine 7.8
mesembrenol 16
OCH
3
OCH
3
N
CH3
OCH
3
OCH
3
N
CH3
O
OCH
3
OCH
3
N
CH3
O
OCH3
OCH3
N
CH3
OH
Table 2. The inhibitory constants (Ki in nM) for three mesembrine alkaloids on the serotonin transporter.
Table 3. PDE4 inhibition of the prototypical PDE4 inhibitor Rolipram and the Sceletium alkaloids
mesembrenone, mesembrine and mesembrenol.
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Nigel Gericke
The results of the broad in vitro screening of the Sceletium extract Zembrin® and some isolat-
ed alkaloids is reported in Harvey et al., 2011. Zembrin® was found to be an inhibitor of the phos-
phodiesterase-4 (PDE4) enzyme in addition to being an SRI (Harvey et al., 2011). The three isolated
mesembrine alkaloids tested were all found to be PDE4B inhibitors, with the most potent of the
three being mesembrenone, which is about one third as potent as the prototypical research PDE4
inhibitor Rolipram (Harvey et al., 2011; MacKenzie and Houslay, 2000). See Table 3 below. US Patent
8,552, 051 (Harvey et al., 2013) discloses the use of mesembrenone as a dual SRI and PDE4 inhibitor.
While SRIs and selective SRIs (SSRIs) are widely used for the treatment of anxiety disorders
and depression, the combination of an SSRI with a PDE4 inhibitor has been argued to have syn-
ergistic therapeutic potential. Repeated treatment with SSRIs can upregulate PDE4 (Ye et al.,
2000), which in turn reduces sensitivity to SSRIs in response to long-term treatment. The treat-
ment with a dual SSRI and PDE4 inhibitors may thus have a therapeutic advantage (Cashman et
al., 2009). Enzymes in the PDE4 family catalyze the hydrolysis of cyclic AMP (cAMP) and have a
critical role in controlling the intracellular concentration of cAMP and increasing phosphoryla-
tion of cAMP-response element-binding protein. PDE4s are found throughout the brain but their
levels are decreased in depressed individuals not on medication, reflecting a downregulation of
the cAMP cascade that can potentially be restored using PDE4 inhibitors. The prototypical PDE4
inhibitor Rolipram has been shown in both animal and clinical studies to have antidepressant
activity (Terburg et al., 2013).
pre-clinical research
Prior to the development of a standardized extract, I sent samples of milled Sceletium tortuosum
plant material to colleagues in Japan who were interested in studying the effect of Sceletium in a vet-
erinary clinic setting. The veterinarians reported that the Sceletium reduced cage stress and travel
stress in cats, and decreased the excessive nocturnal crying and barking of aged cats and dogs with
a clinical diagnosis of dementia. These results have been published in Japanese (Hirabayashi et al.,
2002; Hirabayashi et al., 2004; Hirabayashi et al., 2005).
Sceletium extract Zembrin® was studied in a 14-day repeated oral toxicity study conducted at 0,
250, 750, 2500, and 5000 mg/kg body weight/day (equivalent to total mesembrine alkaloids of 0, 1, 3,
10, and 20 mg/kg bw/day). A 90-day subchronic repeated oral toxicity study was conducted on Sce-
letium extract Zembrin® at 0, 100, 300, 450, and 600 mg/kg bw/day (equivalent to total mesembrine
alkaloids of 0, 0.4, 1.2, 1.8, and 2.4 mg/kg bw/day). Since Sceletium species were known to be psycho-
active, a functional observation battery, including spontaneous locomotor activity measured using
the LabMaster ActiMot light-beam frames system, was employed. Parameters such as locomotion,
rearing behavior, spatial parameters and turning behavior were investigated. No mortality or treat-
ment-related adverse effects were observed in the rats in the 14- or 90-day studies. In the 14- and 90-
day studies, the No Observed Adverse Effect Levels (NOAEL) for Zembrin® were 5000 and 600 mg/
kg bw/d, respectively, the highest dose groups tested (Murbach et al., 2014), equivalent to the NOAEL
for total mesembrine alkaloids of 20 and 2.4mg/kg bw/day.
In a model of restraint-induced psychological stress it was found that a dose of only 5mg/kg
of Sceletium extract (although not stated in the paper, this was Lot #8587 of Zembrin®) given by
gavage reduced restraint stress-induced self-soothing behavior, as well as decreased stress-induced
corticosterone levels (Smith, 2011). This dose is equivalent to a total alkaloid dose of only 20 μg/kg
bw/day.
The effect of single doses of Sceletium extract Zembrin® on rat brain electrical activity was stud-
ied using wireless EEG recordings in free-living rats. 3 doses of the Sceletium extract Zembrin® and
vehicle (0, 2.5, 5.0 and 10.0 mg/kg, equivalent to total mesembrine alkaloids of 0, 10, 20 and 40 μg/
kg) were given by gavage. The resulting electropharmacograms (plotted from Fast Fourier Trans-
formation of the analogue EEG recording for each frequency range) of Zembrin® were compared to
the databased electropharmacograms of reference herbal extracts, dietary ingredients and the phar-
maceutical PDE4-inhibitor Rolipram. Zembrin® had a similar electropharmacogram to the electro-
pharmacograms for extracts of Ginkgo biloba and Rhodiola. A discriminant analysis confirmed these
similarities and also demonstrated that Zembrin® had a similar electropharmacogram to citicoline,
a compound originally developed for cognitive enhancement, and to the PDE4-inhibitor Rolipram.
These results provide support for future translational clinical studies on Zembrin® to investigate
the activity of the extract on cognitive function in Mild Cognitive Impairment, for treating depres-
sion and as an analgesic (Dimpfel et al., 2016).
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Fig. 2 Structures of alkaloids isolated from the genus Sceletium (Gericke & Viljoen, 2008).
The 3a-aryl-cis-octahydroindole
skeleton
4’-O-demethylmesembranol
4’-O-demethylmesembrenone
mesembrane N-demethylmesembrenol
joubertiamine joubertinamine
O-methyldehydrojoubertiamine O-methyljoubertiamine O-methyldihydrojoubertiamine 3’-methoxy-4’-O-methyljoubertiamine
3’-methoxy-4’-O-methyl
joubertiaminol
sceletium alkaloid A4 tortuosamine N-formyltortuosamine N-acetyltortuosamine
4-(3,4-dimethoxyphenyl)-4-
[2-acetylmethylamino)ethyl]
cyclohexanone
4-(3-methoxy-4-hydroxy-
phenyl)-4-[2-acetylmethylamino)
ethyl]cyclohexadienone
“unnamed alkaloid”
dehydrojoubertiamine dihydrojoubertiamine
N-demethylmesembranol hordenine
sceletenone N-demethyl-N-formylmesembrenone O-acetylmesembrenol
4’-O-demethylmesembrenol
mesembrine
mesembrenol mesembranol
mesembrenone ∆7mesembrenone
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Nigel Gericke
Part III
clinical studies on
sceletium extract zembrin®
introduction
The following three case reports on the clinical use of Sceletium, presented at the 4th Interna-
tional Conference on Phytotherapeutics on 23-25 February 2001, Kurrajong, NSW Australia, are the
first clinical case reports for this plant and demonstrate that the plant has therapeutic potential for
anxiety and depression. These historical case reports are given in full from Gericke (2001).
1. patient with a rst episode of severe
depression with marked anxiety
Reported by the author
H.M., a 29-year-old female doctor, presented at my practice asking for a natural treatment for
severe depression. She had had no previous psychiatric history, no history of epilepsy, head injury
or substance abuse, and had a past medical history of atopic eczema and occasional asthma, not
presently on any medication.
main complaint
A four-month period of depressed mood with diurnal variation: the depression was far worse
in mornings, improving somewhat as the day progressed. There was an obvious physiological shift
with decrease in appetite, weight loss and insomnia with difficulty initiating sleep and early morn-
ing waking. Markedly decreased energy and drive were a significant problem for the patient. The
symptoms were accompanied by feelings of anxiety and somatic symptoms of anxiety including
palpitations and epigastric discomfort. Other symptoms of note included suicidal ideation, feelings
of worthlessness, lack of concentration and motivation, tearfulness, emotional lability and general
loss of interest in life.
treatment
The patient requested to be put on Sceletium, having heard about it from a colleague who is a
psychiatrist, and was started on a low dose of 50mg [milled plant material] as a tablet taken in the
mornings.
The patient initially reported a transient increase in anxiety after taking medication, which
would last up to three hours. This effect was no longer apparent after a week of continual use. No
changes in libido were noted, and libido had not been affected by the depression either. A sustained
improvement in mood was reported from somewhere between 1-2 weeks of continual use of 50mg
Sceletium taken daily, with a marked decrease in the generalized anxiety. The patient’s insomnia
improved at the onset of treatment. There was a marked improvement in drive and energy, accom-
panied with a return of interest in the mundane activities that constitute much of everyday living.
The only side effects elicited were the initial transient increase in anxiety and some initial appe-
tite suppression, neither of which was severe enough to warrant discontinuation of treatment, and
both of which were no longer apparent after the first two weeks of treatment.
Conclusion
A low dose of Sceletium (50mg daily) taken orally as a tablet proved to be a very effective anxiolyt-
ic and mood elevator in a first episode of a major depression. The Sceletium was discontinued after
4 months of continual use with no signs or symptoms of withdrawal, and there has so far (about 6
months) been no return of symptoms of anxiety or depression.
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2. patient with postnatal
major depressive disorder.
Reported by Dr Olga Gericke MUDR (Vienna) FC Psych. (SA)
A 28-year-old married housewife with two children, aged three and a half and two months old
respectively, presented with depressive symptoms that she had had since the seventh month of
her second pregnancy. Complaining of depressed mood, increased sleep, overeating, low energy,
increased anxiety to the point of perceptual illusions and depersonalization, feelings of worthless-
ness, psychomotor agitation, thoughts of death, decreased ability to concentrate and forgetfulness.
She also complained of inability to bond with her newborn and felt very irritable and aggressive to-
wards her three-year-old. The patient had self-medicated with St John’s Wort (Hypericum perforatum)
over the last two weeks, with minimal effect.
past psychiatric history
Severe postnatal depression after her first child, needed hospitalization, was on Aurorix (Mo-
clobemide) for two years with limited success and discontinued it due to side effects. Her first onset
of depression was at age 16, which was treated with Amitryptyline and therapy.
past medical history
Pre-eclampsia with first pregnancy and currently hypertension, obesity.
habits: nil.
Present medication: ACE inhibitor for hypertension.
Family and social: Disruptive upbringing, mother suffered from severe depression and
was hospitalized frequently, both sisters suffer from panic disorder.
diagnosis
• Major depressive disorder, recurrent, severe, postnatal onset
• Borderline personality traits
• Hypertension
treatment
The patient was started on Sceletium 50 mg [milled plant material] in the morning and at lunch-
time. The immediate effect (the first day of treatment) was mood elevation, significantly decreased
sleep (from 14 hours a day to eight hours a day) and increased energy. The patient voluntarily started
doing housework again. After four weeks of treatment, symptoms of mild depression and anxiety
were present again. After six weeks of treatment with Sceletium, and supportive therapy and group
sessions with a postnatal depression support group, the patient appeared to be fully recovered and
is presently well on a maintenance dose of 50 mg Sceletium twice a day.
comment
To date, I have successfully used Sceletium in 10 patients with a diagnosis of Major Depressive
Disorder according to DSM-IV criteria. My patients are usually more severely depressed or anxious
than the clients of psychologists and patients of general practitioners, and most of them have been
on various pharmaceutical antidepressants before. Most of the patients had a strong anxiety com-
ponent to the depression. Sceletium alleviates anxiety very quickly, though in sensitive individuals
the first dose can actually increase the anxiety for about half an hour, after which it is relaxing. My
starting dose is usually 50mg in the morning and most patients increase it to an additional 50mg at
lunchtime or early afternoon. If taken later, it can cause insomnia in some patients. In some patients
I have had to increase the dose to 100mg/12 hours.
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3. case report by cheryl inggs
B.A. Honours, MA(Clin. Psych.) Rhodes
The client is a 19-year-old university student who started therapy (once a week) towards the end
of her second year (1999). She completed her bachelor’s degree at the end of 2000 and has just en-
tered her Honours degree.
the client presented with the following:
Axis I : Dysthymia. She felt despondent and “trapped inside”, she isolated herself and “couldn’t
see a way out”, was sometimes tearful, alternating with an emptiness inside and a pervasive sense of
sadness; she had low self-esteem, a loss of interest in activities with social withdrawal, loss of moti-
vation, some distractability and short-term memory loss, tiredness, lethargy, hypersomnia and loss
of appetite with occasional “comfort eating” mostly of junk food. There was no suicidal ideation.
Axis II : Borderline Personality. Described feeling “out of touch” and depersonalized, with some
self-mutilation (scratching her upper arm and wrist). Some impulse binge-drinking when socializ-
ing. She had tried “ecstasy” (MDMA) and indulges in marijuana very occasionally. A baseline mood
of depression alternating with anxiety and a feeling of tension particularly around her studies and
exam performance (sweaty palms, constipation and hair loss). Feelings of emptiness and fear of
abandonment. Inappropriate and intense anger. Battling with a sense of self and identity, feeling
unsure of who she is, feeling distant, isolated and lonely.
therapeutic issues
The client clearly presented with long-standing dysthymia and some anxiety. She had also been
sexually abused from age 12-15. She is the middle child and only daughter of an emotionally absent
father and a career-oriented mother on whom the client is emotionally dependent. She vacillates
between idealizing her mother when she is available and feeling abandoned by her when she is un-
available. The client carries a great deal of anger, and has body-image problems coupled with a fear
of sexual intimacy.
treatment
The therapeutic approach was from a self-psychology model providing a containing environ-
ment with careful intervention and gentle interpretation. The client was able to be very insightful
but lacked the capacity to process the insight in any meaningful way. She presented with an ongoing
sense of emptiness and depersonalization, with a deep despondency and hopelessness. Sceletium
was administered as a 50mg tablet daily from October 2000. Within ten days, the patient said that
her mood had lifted and that she felt slightly less depersonalized. She was able to feel more focused,
more engaged and not so socially “distant.” She doubled her dose to two 50-mg tablets daily just
prior to her examination (November 2000) and described feeling less anxious and more able to cope
with her usual examination anxiety. An interesting development on Sceletium was that she described
feeling less inclined to overindulge in alcohol (she said that it didn’t taste as good).
conclusion
The client clearly has personality problems that require ongoing therapy. However, what is
significant is that the Sceletium certainly helped her feel more contained, lifted her mood and also
helped with anxiety. There is a sense in which the Sceletium has stabilized her to the point where we
were able to actively engage in some of the more pressing therapeutic issues.
The rapid improvements in mood and anxiety in these initial three patients provided the impe-
tus for the development of the proprietary standardized and characterized Sceletium extract Zem-
brin® for formal clinical research.
safety & tolerability (Nell et al., 2013)
The safety and tolerability of Sceletium extract Zembrin® was studied in the first formal clinical
study of a Sceletium extract. In this randomized, double-blind, placebo-controlled clinical study,
two doses of Zembrin® (8mg and 25mg, equivalent to total mesembrine alkaloids of 32μg and 100μg
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respectively) were taken orally once daily for three months by healthy adult volunteers. No efficacy
variables were assessed. The extract was found to be safe and well tolerated. An interesting aspect
of the study was unsolicited positive effects on well-being noted in patients’ side-effect diaries by
some participants taking the extract, including improved coping with stress and improved sleep at
night.
pharmaco-fmri study (Terburg et al., 2013)
The acute effects of extract Zembrin® were investigated in a pharmaco-fMRI study focused on
anxiety-related activity in the amygdala and the connected neuro-circuitry. In a double-blind, pla-
cebo-controlled cross-over design, 16 healthy university student participants were scanned during
performance of an emotion-matching task under low and high perceptual loads. Amygdala reactiv-
ity to fearful faces under low perceptual load conditions was attenuated, with a decreased blood ox-
ygenation level-dependent (BOLD) signal for Zembrin® compared to placebo on low-load exposure
to fearful faces compared with neutral challenges in the bilateral amygdala (P<0.01) after a single
25mg (equivalent to 100μg total mesembrine alkaloids) dose of Zembrin®. Follow-up connectivity
analysis on the emotion-matching task demonstrated that amygdala–hypothalamus coupling was
also reduced. These results demonstrated, for the first time, the attenuating effects of an extract of
Sceletium on the threat circuitry of the human brain and provided supporting evidence that this
extract may have anxiolytic potential by attenuating subcortical threat responsivity. These results
are consistent with the in vitro dual serotonin reuptake inhibition and PDE4 inhibition reported by
Harvey et al., 2011.
cognition-enhancing activity (Chiu et al., 2014).
In a randomized double-blind placebo-controlled cross-over clinical study normal healthy older
subjects (total n=21) (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) received either a 25 mg
capsule of Sceletium extract Zembrin® (equivalent to 100mg total mesembrine-alkaloids) or place-
bo capsule once daily for 3 weeks. The primary endpoint was to examine the neurocognitive effects
of the extract using the CNS Vital Signs battery of tests. Zembrin® at 25 mg daily dosage signifi-
cantly improved executive function (p0.022) and cognitive set flexibility (p0.032) compared with
the placebo group. Positive changes in mood and sleep were also found, and the extract was well
tolerated. It was concluded that PDE-4 inhibition with the resulting cAMP-CREB cascade may play
a role in these cognitive enhancing effects of Zembrin®.
activity on eeg, psychometry, and anxiety
(Dimpfel et al., 2017).
In a randomized, double-blind, placebo-controlled clinical study, the effect of 25mg or 50mg of
Zembrin® (equivalent to 100μg and 200μg of total mesembrine alkaloids, respectively) was studied
in comparison to placebo after daily repetitive intake for 6 weeks. Sixty healthy male (n = 32) and fe-
male (n = 28) subjects between 50 and 80 years old (59.7 ± 5.43 and 56.7 ± 5.88 years, respectively) were
recruited. The EEG was recorded bipolarly from 17 surface electrodes. Six cognitive tests were per-
formed: d2-test, memory test, calculation performance test, reaction time test, number identifying
test and number connection test. Three questionnaires were included: Profile of Mood States, Ham-
ilton Anxiety Rating Scale (HAM-A) and a sleep questionnaire. Quantitative EEG revealed increases
of delta activity during performance of the d2-test, the number identification and number connec-
tion tests in the fronto-temporal brain region. Higher theta activity was seen during relaxation and
performance of the d2-test after intake of 50mg of Zembrin®. Statistically conspicuous increases of
alpha1 spectral power were seen in the relaxed state. With respect to alpha2 spectral power, larger
increases were observed in the centro-occipital region. Discriminant analysis of the EEG data re-
vealed a projection of the Zembrin® data into the vicinity of the EEG data plot for a ginkgo-ginseng
combination. Statistically significant improvement during performance of the arithmetic calcula-
tion test and number connection test was documented. The HAM-A anxiety score revealed a statis-
tically significant decrease (p = 0.03) after six weeks intake within the 50mg Zembrin® group. The
results indicate that Zembrin® improves some aspects of cognitive function, and decreases anxiety
in healthy older adults.
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Part IV
kanna and mesembrine-alkaloids:
possible futures
legal highs
Legal highs are typically sold by online Smart Shops and may be broadly defined psychoactive
substances which have not (in some cases not yet) been proscribed by laws or regulations, and are
used to elicit a desired state of mind which may be stimulated, euphoric, empathogenic or entacto-
genic, entheogenic, sedated or a combination. The substances may be isolated natural compounds,
synthetic or semi-synthetic compounds, extracts of plants or fungi, or whole or minimally pro-
cessed plant or fungal material. The first online sales of Sceletium plant material, originally from
40kg of plant material cultivated by Grassroots Natural Products for Pharmacare Ltd., began in 1999
by Om-Chi Herbs in Eugene, Oregon in the USA, and by Conscious Dreams in Amsterdam in the
Netherlands, later to be followed by Botanic Art in the Netherlands. These online stores played a
major role in introducing kanna to a wide international audience. It is now eighteen years later, and
there are many online Legal Highs and botanical supply stores selling fermented and unprocessed
kanna as milled plant material and extracts. From about 2004, there seems to have been a marked
increase in the use of kanna in the South African trance scene, where powdered kanna is used as
a snuff, or mixed with marijuana for smoking to induce a “chilled” state of mind and to decrease
anxiety in people who get more anxious while smoking marijuana. Kanna is used instead of MDMA
by some people in the South African trance scene, and to reduce the come-down after an MDMA
session by others. By 2017, kanna use had become part of the international trance and party scene,
with use of kanna apparently being well known in Ibiza, Spain.
A recent development of serious concern is the online sale of concentrated to highly concentrat-
ed extracts sold as kanna which are of uncertain botanical origin, unknown total alkaloid content,
unknown relative alkaloid composition and unknown stability. A search of Sceletium extracts on
Alibaba.com shows a wide variety of “Sceletium” extracts, many produced in China (some accom-
panied by photographs of flowers that are definitely not Sceletium flowers). This includes some
touted as “100:1” extracts (presumably a raw material to extract ratio, weight/weight) and some pur-
porting to be “98% mesembrine” (Alibaba.com, 2017). There is already nascent legal and regulatory
flagging of kanna, and overconcentrated extracts carry a potential for serious adverse events. The
analysis of Sceletium alkaloids for future forensic toxicology and legislation purposes has already
been described (Roscher et al., 2012), and the United Nations Office on Drugs and Crime (UNODC) is-
sued a list of 20 plant-based substances of concern in 2013, including Sceletium. The metabolism of
Sceletium alkaloids was investigated in rat urine and pooled human liver preparations (Meyer et al.,
2015) because of the increasing popularity of kanna as a legal high, and the metabolites, especially
in the urine, would be good analytical targets for forensic and legal purposes. Sceletium has already
attracted the attention of the Drug Enforcement Agency (DEA) of the United States, featuring in a
presentation by a forensic chemist at the DEA Special Testing and Research Laboratory with the
title, “Novel Plant Hallucinogens and Plant-Derived Highs” (Dye, undated presentation). Surpris-
ingly, Amazon.com has prohibited the sale of kanna and cited it as an example of a plant-derived
product that simulates the effect of illegal drugs (Amazon.com, 2017). An additional legal and regu-
latory threat is the potential for adverse reactions from adulterated kanna. During an investigation
into the wide phytochemical variability of kanna available from online stores, the alarming discov-
ery was made that one of the samples of kanna had been adulterated with the stimulant ephedrine
(Lesiak et al., 2016).
Notwithstanding the forensic and regulatory flagging, the use of isolated pure mesembrine al-
kaloids may ultimately become more widely available to the general public via the rapidly grow-
ing vaping and electronic cigarettes industries, evidenced by two recent US Patent Applications for
electronically heated aerosol systems filed by Philip Morris Products S.A., Neuchatel, Switzerland,
with mesembrine given as one of the examples of active ingredients to be vaporized (Schneider J-C.
et al., 2016; Thorens and Cochand, 2016).
Supplement
The first commercial supplement product containing Sceletium was put on the South African
market in 2001 by a South African company I founded, Phyto Nova (Pty) Ltd. This product consisted
simply of a low dose of 50mg tablets of milled cultivated Sceletium tortuosum, with the traditional
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uses stated as stress relief and mood elevation. The recommended dose was specified as one to two
tablets daily. Tablets containing 25mg of the standardized Sceletium extract Zembrin® were first
launched on the South African market in 2010. The recommended dose is 25-50mg taken once a day
(containing 100-200 μg total mesembrine alkaloids). The tablets are used for stress, anxiety and
mild to moderate depression. In South Africa, these tablets are popular during exam time, used by
university students and matriculated school children for improving concentration and reducing
stress while studying for exams. The South African National Defence Force has included tablets
containing Zembrin® in its code of products that can be prescribed by military psychiatrists and
physicians.
A highlight of the Sceletium project was the marketing authorization given to Zembrin® in 2014
by the Natural and Non-Prescription Health Products Directorate of Health Canada, issued as Prod-
uct Licence number 80052770 on 29 July 2014, for capsules containing 25mg extract, a daily dose of
100μg mesembrine alkaloids.
There are now many brands of tablets, capsules, tinctures and teas of functional food and dietary
supplement products containing Sceletium plant material, Zembrin®, and other extracts on the
market, mainly in the United States, with lesser sales in much smaller markets including Canada,
South Africa, Malaysia and Japan. The cost of formally addressing the diverse national regulatory
requirements has limited the international penetration of Sceletium supplements, and it is not clear
if companies will be willing to invest in addressing these requirements in the face of increasing
competition from what has essentially become a generic botanical dominated by internet sales of
these products directly to consumers.
We are living in a fast-paced, highly stressed and uncertain world, challenged with electronic
media competing for mindspace, and assaulted daily with news of dramatic geopolitical, economic,
social, climatic and environmental changes. Simultaneously, we are on the threshold of the Fourth
Industrial Revolution, which is fundamentally changing our lives, our work, our relationships and
blurring the boundary between ourselves and our technologies. Low doses of mesembrine alkaloids,
probably in the range of only 200μg-400μg and perhaps best in a sustained-release dosage form,
have great potential to safely enhance the daily quality of people’s lives. More than twenty years of
work on this plant has shown me that we have not yet begun to realize the potential that supple-
ments of Sceletium or Sceletium alkaloids hold for:
• reducing stress and situational anxiety
• enhancing well-being
• elevating mood in mild to moderate depression
• enhancing cognitive function
• reducing alcohol and drug abuse
• facilitating psychotherapy
• facilitating meditative and spiritual states
medicine
To date there have been no clinical trials on extracts of Sceletium in a clinical population. Two
recent clinical case reports are presented here, where extract Sceletium tortuosum Zembrin® was used
by my wife Dr. Olga Gericke in her integrative psychiatric practice in Cape Town (Gericke et al., 2017).
case report 1
A 40-year-old married housewife with two children, aged 6 and 9, was referred to Dr.
Olga Gericke for medication review. Her history included recurrent major depressive
disorder since age 17, postpartum depression and social anxiety disorder. For the pre-
vious eight years, she had been on citalopram 20mg per day, which had adequately
treated her depression and social anxiety. However, the patient found the side effects
difficult to tolerate: loss of libido, emotional blunting and weight gain. Two attempts
to discontinue citalopram resulted in recurrence of her depressive symptoms within
four months, necessitating resumption of the medication. During consultation, the
patient stated she was determined to wean herself off citalopram. After being coun-
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Nigel Gericke
seled on pharmaceutical and botanical treatment options, the patient opted for a trial
of 25mg extract of Sceletium tortuosum (Zembrin®). Citalopram was reduced to 10mg
daily for one week and then discontinued while starting 50mg of Sceletium, which was
increased to a daily maintenance dose of 75mg. At one-month follow-up, she reported
no anxiety/depressive symptoms, though she experienced occasional mild episodes of
social anxiety, which she found easy to tolerate. Her libido had returned to normal,
she felt much more in touch with her feelings and had lost two kilograms of weight.
During the following month, her mood had slightly lowered, but this responded well
to an increase of the Sceletium extract to 100mg per day. Eight months after initial
assessment, she remained in remission on 100mg per day Sceletium extract Zembrin®
with no side effects.
case report 2
A 45-year-old married man, visiting South Africa from Europe, was referred to Dr. Olga
Gericke by a general practitioner for assessment of depressive symptoms which de-
veloped after the birth of the patient’s child eighteen months previously. Two prior
episodes of depression five years and seven years before were clearly associated with
stressors and had resolved without treatment. He had seen a psychotherapist for two
years in his country of origin. There was no history of medical illness and routine
blood tests were normal. There was a family history of depression but no history of
substance abuse. The patient had recently tried self-medicating with a combination
product of Sceletium tortuosum and Avena sativa, but found it too sedating. Treatment
was initiated with 50mg per day Sceletium tortuosum extract and increased to 100mg a
day. In addition, the patient was seen for weekly supportive psychotherapy sessions.
Within four weeks, his depressive symptoms remitted and he was discharged from
the practice after six weeks when he was returned to his country of origin. He was ad-
vised to continue the 100mg Sceletium tortuosum extract daily and to seek psychiatric
follow-up on his return home.
Standardized and characterized Sceletium extracts clearly have great potential as safe, effective
botanical medicines for treating clinical anxiety and depression, and integrating extracts of Scele-
tium into psychiatric clinical practice has been described based on Olga’s fifteen years of experience
with Sceletium in her practice in Cape Town, and the clinical experience of Dr. Richard P. Brown, a
psychopharmacologist and integrative psychiatrist in New York who has prescribed Sceletium in
more than 30 patients during the past 4 years (Gericke et al., 2017).
While standardized Sceletium extracts have great potential to be used as botanical medicine to
treat clinical anxiety and depressive states, it is not clear if this potential will ever be realized. The
cost of developing the clinical evidence of safety and efficacy to achieve marketing authorization
for a botanical medicine is prohibitive, the quality issues of polymolecular botanical medicines
continue to be a major challenge, and the regulatory pathway to achieve registration as a botanical
medicine is not as clear or as harmonized internationally as for single chemical entities. In the last
two decades, the US Food and Drug Administration has only approved two botanical drugs; the
first botanical drug approved by the FDA was Veregen®, a treatment for genital and perianal warts
that is derived from a green tea extract (Cameia sinensis Kuntze), and a number of years later the
FDA approved Fulyzaq™, a drug for HIV-associated diarrhea, extracted from the latex of the South
American tree (Croton lechlerii Müll. Arg) (Ahn, 2017).
Future approved medicines derived from Sceletium are more likely to be developed from isolat-
ed pure alkaloids, their metabolites, or from semi-synthetic derivatives. Pathways for the synthe-
sis of mesembrine and related alkaloids have been described from the early 1960s. A review of the
synthesis of mesembrine, for example, includes more than thirty described pathways, including
isomer-selective synthesis (Zhao et al., 2010). While there is a fairly extensive literature on the chem-
istry and synthesis of these compounds, the pharmacology of isolated compounds has hardly been
explored. The pharmacology of metabolites of these compounds presents a rich field for psychoac-
tive new drug discovery.
Distillation of two decades of experience of indigenous uses, in vitro pharmacology, pre-clini-
cal studies, anecdotal reports, clinical case studies and pilot randomized controlled clinical trials
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Nigel Gericke
suggest that isolated Sceletium alkaloids (and their metabolites and analogues) have enormous po-
tential for the development of rapidly acting psychoactive drugs with a low side-effect profile for:
• Major Depressive Disorder
• Generalised Anxiety Disorder
• Attention Deficit Disorder and Attention Deficit Hyperactivity Disorder
• Post-Traumatic Stress Disorder
• Mild Cognitive Impairment
• Neuroprotection
• Controlling appetite and craving in weight management programs
• Addiction management, including opioid addiction
• Chronic pain
• Schizophrenia
My hope is that this paper will stimulate further academic and pharmaceutical research to real-
ize the potential of Sceletium extracts and mesembrine-type alkaloids for preventing, treating and
ameliorating diverse mental health diseases, and for enhancing the quality of life of all people.
acknowledgments
Family, friends and colleagues are thanked for their contribution to this Sceletium odyssey:
Aaron Santana, Abdulgaseeb Jacobs, Abraham van Rooyen, Alan Gray, Alan Harvey, Alex Schauss,
Alison Dyer, Alvaro Viljoen, Andrew Tully, *Mark Tully, *Andries Steenkamp, Antonio Bianchi, Ash-
ley Mashigo, Bani Isaac Mayeng, Barbara Davis, Beatrice Molac, Beatriz Ercilla, Ben-Erik van Wyk,
Bruce Gordan, C.C. Kennedy, Carine Smith, Carl Albrecht, Cheryl Inggs, Chris Watson, Christine
Tomcheck, Credo Mutwa, Dan Stein, David Terburg, Dennis McKenna, Deon Hofmeyr, Diana-Lee
Simon, Dick Doorn, Dierdre Allen, Dorris Schroeder, *Earle Graven, Edda Fiegert, Emmanuel Shi-
kanga, Eric Anderson, Eric Gericke, Fabio Ravanello, Fabio Soldati, Fiona Archer, George David-
son, *Gert Dirkse, *Greg McCarthy, Guy Wertheim-Aymes, Hans van den Hurk, Hannes de Lange,
Haylene Nell, *Hibiki Kurono, Holly Bayne, Ingrid Keplinger-Dimpfel, Iris Freie, Isadore Kanfer, Jack
van Honk, Jap-Jap Klaasse, Jerry Cott, John Endres, *John Winslow, Julia Wiebe, Kenjiro Shimada,
Kenzi Loke, Kia Gericke, Laubi Walters, *Lawrence Penkler, Leana Cloete, Leana Bronkhorst, Lin-
da Brady, Lisa Garson, Lisa Meserole, Lita Cole, Lodewyk Mories, Manuel Lopez-Romero, Marena
Manley, Marion Weston, Mark Blumenthal, Maryna Swart, Matt Tripp, Michel Woodbury, Michelle
Gericke, Miguel Jimenez del Rio, Myke Scott, Ncindani Maswanganyi, Neal Craft, Nicky Gericke,
Nuri Fraile Lopez, Olga Gericke, Patricia Garberg, Paul Flowerman, Paul Jonker, Pete Backwell, Peter
Williams-Ashman, Pippa Skotnes, Richard Brown, Roberto Jimenez del Rio, Robb Snaddon, Roger
Chennels, Roger Stewart, Roy van Brummelen, Rudi Giger, *Ryo Yonemoto, Satoru Furukawa, Seth
Flowerman, Simon Chiu, Sinobu Kurono, Srinivas Patnala, Tanausú Vega, Timothy Murbach, Ulrich
Feiter, Veronica Napier, Vladimir Badmaev, Wilfried Dimpfel, William Emboden.
*Deceased.
references
Ahn, K., 2017. The worldwide trend of using botanical drugs and strategies for developing global drugs. BMB reports
50(3): 111-116.
Alibaba.com, 2017. https://www.alibaba.com/trade/search?fsb=y&IndexArea=product_en&CatId=&SearchText=scele-
tium+extracts&isGalleryList=G Accessed 20th April 2017.
Amazon.com, 2017. Drugs and drug paraphernalia. Examples of prohibited listings. https://www.amazon.com/gp/help/
customer/display.html/ref=hp_rel_topic?ie=UTF8&nodeId=200277220 Accessed 7th April 2017.
Archer, F.M., 1994. Ethnobotany of Namaqualand: The Richtersveld (Master of Arts dissertation, University of Cape Town).
Cashman, J.R., et al., 2009. Stereoselective inhibition of serotonin reuptake and phosphodiesterase by dual inhibitors
as potential agents for depression. Bioorganic & Medicinal Chemistry 17(1), 337-343.
Chiu, S., et al., 2014. Proof-of-concept randomized controlled study of cognition effects of the proprietary extract
Sceletium tortuosum (Zembrin) targeting phosphodiesterase-4 in cognitively healthy subjects: implications for
Alzheimer’s Dementia. Evidence-Based Complementary and Alternative Medicine Vol. 2014,1-10.
Collot, A.G., 1856. A New and Improved Standard French and English and English and French Dictionary. C.G. Henderson and
Company, Philadelphia.
148
Nigel Gericke
De La Caille, M. l’Abbé., 1763. Journal Historique Du Voyage Fait Au Cap De Bonne Esperance. Academie Des Sciences,
Paris.
Digby, A., 2005. 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. Social History of Medicine 18, 439–457.
Digital Bleek & Lloyd. http://lloydbleekcollection.cs.uct.ac.za/xam.html. Accessed 21 June 2017.
Dimpfel, W., et al., 2016. Electropharmacogram of Sceletium tortuosum extract based on spectral local field power in
conscious freely moving rats. Journal of Ethnopharmacology 177, 140-147.
Dimpfel, W., et al., 2017. Effect of Zembrin® on Brain Electrical Activity in 60 Older Subjects after 6 Weeks of Daily
Intake. A Prospective, Randomized, Double-Blind, Placebo-Controlled, 3-Armed Study in a Parallel Design. World
Journal of Neuroscience 7, 140-171.
Dragendorff, G., 1898. Die Heilpflanzen Der Verschiedenen Völker Und Zeiten. Verlag Von Ferdinand Enke, Stuttgart.
Dye, E. Undated presentation. Novel hallucinogens and plant-derived highs. Drug Enforcement Agency. https://www.
nist.gov/sites/default/files/documents/oles/NIST-Novel-Hallucinogens-and-Plant-Derived-Highs-Final.pdf
Accessed 15 April 2017.
Forbes, E.S. (Ed.)., 1986. Carl Peter Thunberg. Travels at the Cape of Good Hope 1772–1775. Second Series No. 17, Van Riebeeck
Society, Cape Town.
Gerbaulet, M., 1996. Revision of the genus Sceletium N.E. Br. (Aizoaceae). Botanische Jahrbücher 118, 9–24.
Gericke, N., 1995. Sceletium Project. Investigation of a Traditional Herbal Sedative. Unpublished research report for
South African Druggists Ltd., 30 May 1995.
Gericke, N., 2001. Clinical application of selected South African medicinal plants. Australian Journal of Medical Herbalism
13, 3–17.
Gericke, N., 2002. Plants, products and people: southern African perspectives, in: Advances In Phytomedicine Volume 1.
Ethnomedicine And Drug Discovery. Iwu, M.M., Wootton, J.C. (Eds.), Elsevier, Amsterdam.
Gericke, N., 2011. Muthi to medicine. South African Journal of Botany 77(4), 850-856.
Gericke, N., 2014. Ethnobotanical records from a corporate expedition in South Africa in 1685. Herbalgram. Journal of
the American Botanical Council 102, 48-61.
Gericke, N., Van Wyk, B.-E., 1999. Pharmaceutical compositions containing mesembrine and related compounds. US
Patent 6,288,104.
Gericke, N., and van Wyk, B.-E., 2000. People’s Plants. A Guide To Useful Plants Of Southern Africa. Briza, Pretoria.
Gericke, N., and Viljoen, A.M., 2008. Sceletium—a review update. Journal of Ethnopharmacology 119(3), 653-663.
Gericke, O., et al., 2017. Sceletium tortuosum, in: Complementary and Integrative Treatments in Psychiatric Practice. Gerbarg,
PL, Muskin PR, Brown RP (Eds.), American Psychiatric Association Publishing, Arlington, VA.
Gordon, D., 1996. From rituals of rapture to dependence: the political economy of khoikhoi narcotic consumption,
c.1487–1870. South African Historical Journal 35, 62–88.
Gunn, M., Codd, L.E., 1981. Botanical Exploration of Southern Africa. A.A. Balkema, Cape Town.
Harvey, A.L., et al., 2011. Pharmacological actions of the South African medicinal and functional food plant Sceletium
tortuosum and its principal alkaloids. Journal of Ethnopharmacology 137(3), 1124-1129.
Harvey, A., et al., 2013. Pharmaceutical compositions containing mesembrenone. U.S. Patent 8,552,051.
Herre, H., 1971. The Genera Of The Mesembryanthemaceae. Tafelberg, Cape Town.
Hirabayashi M., et al., 2002. Clinical application of South African tea on dementia dog. Japanese Journal of Small Animal
Practice 21, 109–113. [Japanese]
Hirabayashi M., et al., 2004. Clinical effects of South African tea for cat. Japanese Journal of Small Animal Practice 23,
85–89. [Japanese]
Hirabayashi M., et al., 2005. Clinical effects of South African Tea for dementia animal. Japanese Journal of Small Animal
Practice 24, 27–31. [Japanese]
Hobbs, C.E., 1876. C.E. Hobbs’ Botanical Hand-Book. C.E. Hobbs, Boston.
Holmes, E.M., 1874. Materia Medica Notes. American Journal of Pharmacy Vol. XlVI (1), 286.
Iatridis, K., Schroeder, D., 2016. Responsible Research and Innovation in Industry. The Case for Corporate Responsibility Tools.
Springer, Cham, Heidelberg, New York, London.
Jacobsen, H., 1960. Handbook of Succulent Plants. Vol. III. Mesembryanthemums (Ficoidaceae). Blandford Press, London.
Jeffs, P.W., et al., 1982. Sceletium alkaloids. Structures of five new bases from Sceletium namaquense. Journal of Organic
Chemistry 47, 3611–3617.
Juritz, C.F., 1905. Report of the joint meeting of the British Association for the Advancement of Science and the South African
Association for the Advancement of Science 1, 231.
Klak, C., Bruyns, P.V., 2013. A new infrageneric classification for Mesembryanthemum (Aizoaceae: Mesembryan-
themoideae). Bothalia 43 (2), 197-206.
Kolben, P., 1731. The Present State of the Cape of Good Hope. Translated from German by Mr. Medley. W. Innys, London,
210-213.
Krstenansky, J.L., 2017. Mesembrine Alkaloids: review of their occurrence, chemistry, and pharmacology. Journal of
Ethnopharmacology 195, 10-19.
Laidler, P.W., 1928. The magic medicine of the Hottentots. South African Journal of Science 25, 433–447.
Lesiak, A.D., et al., 2016. Direct analysis in real-time high-resolution mass spectrometry as a tool for rapid character-
ization of mind-altering plant materials and revelation of supplement adulteration–the case of Kanna. Forensic
science international 260, 66-73.
MacKenzie, S.J., Houslay, MD, 2000. Action of Rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on
the phosphorylation of cAMP-response-element binding protein (CREB) and p38 mitogen-activated protein
(MAP) kinase in U937 monocytic cells. Biochem J. 347 (Pt 2), 571–578.
Marloth, R., 1917. The Flora Of South Africa. Dictionary of The Common Names Of Plants. Specialty Press of South Africa,
Cape Town, 105.
149
Nigel Gericke
Meiring, I., 1896. Notes on some experiments with the active principle of Mesembrianthemum tortuosum, L. Transac-
tions of the South African Philosophical Society Volume IX, 48–50.
Meyer, G.M., et al., 2015. GC-MS, LC-MSn, LC-high resolution-MSn, and NMR studies on the metabolism and toxico-
logical detection of mesembrine and mesembrenone, the main alkaloids of the legal high “Kanna” isolated from
Sceletium tortuosum. Analytical and bioanalytical chemistry 407 (3), 761-778.
Moreland, W.H. (Ed.), 1934. Peter Floris, His Voyage to the East Indies in the Globe, 1611-1615. The Contemporary Translation of
His Journal. Hakluyt Society, London, 4-5.
MSS BC151 006, Manuscript and Archives Department of the Libraries, University of Cape Town.
Murbach, T.S., et al., 2014. A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zem-
brin®) in rats. Food and Chemical Toxicology 74, 190-199.
Nell, H., et al., 2013. A randomized, double-blind, parallel-group, placebo-controlled trial of extract Sceletium tortuosum
(Zembrin) in healthy adults. The Journal of Alternative and Complementary Medicine 19(11), 898-904.
Nicholl, J.M., 1895. Botanical Ready Reference. Murray & Nicholl Manufacturing Company, Chicago.
Nortje, J., 2011. Medicinal Ethnobotany of the Kamiesberg, Namaqualand, Northern Cape Province (Doctoral dissertation,
MSc thesis), University of Johannesburg.
Nortje, J.M., Van Wyk, B.-E., 2015. Medicinal plants of the Kamiesberg, Namaqualand, South Africa. Journal of Ethnophar-
macology 171, 205-222.
Pappe, L., 1868. Florae Capensis Medicae, 3rd ed., Prodromus. An Enumeration of South African Plants used as Remedies by the
Colonists of the Cape of Good Hope. W. Brittain, Cape Town.
Patnala, S., Kanfer, I., 2010. HPLC analysis of mesembrine-type alkaloids in Sceletium plant material used as an African
traditional medicine. Journal of Pharmacy & Pharmaceutical Sciences 13(4), 558-570.
Prader-Samper, José M. de., 2007. The plant lore of the /Xam San: //Kabbo and ≠Kasiŋ’s identification of “Bushman”
medicines. Culturas Populares. Revista Electrónica 4, 1-17. http://www.culturaspopulares.org/textos4/articulos/
deprada.pdf ISSN: 1886-5623.
Purchas, S., 1625. Purchas His Pilgrimes. In Five Bookes. Printed by William Stansby for Henrie Fetherstone, London. Book
One, 528.
Rimington, C., Roets, C.G.S., 1937. Notes upon the isolation of the alkaloidal constituent of the drug “channa” or “kou-
goed”. Onderstepoort Journal of Veterinary Science and Animal Industry 9, 187-191.
Roscher, J., et al., 2012. Forensic analysis of mesembrine alkaloids in Sceletium tortuosum by nonaqueous capillary elec-
trophoresis mass spectrometry. Electrophoresis 33(11), 1567-1570.
Schneider, J-C, Poljoux, J., Fernando,F., Greim, O. 28 September 2016. Heating assembly for an aerosol generating sys-
tem. European Patent Application EP20130821804
Scott, G., Hewett, M.L., 2008. Pioneers in ethnopharmacology: the Dutch East India Company (VOC) at the Cape from
1650 to 1800. Journal of Ethnopharmacology 115(3), 339-360.
Serton, P., Raven-Hart, W.J. de Kock en E.H. Raidt (Eds.), 1971. François Valentijn, Beschryvinge van de Kaap der Goede Hoope.
Deel I. Van Riebeeck Society, Cape Town.
Shikanga, E.A., et al., 2012. Validated RP-UHPLC PDA and GC–MS methods for the analysis of psychoactive alkaloids in
Sceletium tortuosum. South African Journal of Botany 82, 99-107.
Smith, C., 2011. The effects of Sceletium tortuosum in an in vivo model of psychological stress. Journal of Ethnopharmacol-
ogy 133(1), 31-36.
Smith, C.A., 1966. Common Names of South African Plants. Botanical Survey Memoir 35. Government Printer, Pretoria.
Smith, M.T., et al., 1996. Psychoactive constituents of the genus Sceletium NE Br. and other Mesembryanthemaceae: a
review. Journal of Ethnopharmacology 50(3), 119-130.
Tachard, G., 1686. Voyage de Siam, Des Pères Jesuites, Envoyez par le Roy aux Indes & à la Chine. Arnold Seneuze and Daniel
Horthemels, Paris, 102.
Terburg, D., et al., 2013. Acute effects of Sceletium tortuosum (Zembrin®), a dual 5-HT reuptake and PDE4 inhibitor, in
the human amygdala and its connection to the hypothalamus. Neuropsychopharmacology 38(13), 2708-2716.
Thorens, M., Cochand, O., 24 March 2016. Electronically heated aerosol delivery system. United States Patent Applica-
tion 20160081395.
Tully, W., 1858. Materia Medica or Pharmacology And Therapeutics. Jefferson Church MD, Springfield, 823.
UNODC, 2013. The Challenge of New Psychoactive Substances. List of Plant-based Substances, 101-102.
Waterhouse, G., et al., 1979. Simon van der Stel’s Journey to Namaqualand in 1685. Human & Rousseau, Cape Town.
Watt, J.M., and Breyer-Brandwijk, M.G., 1962. The Medicinal and Poisonous Plants of Southern and Eastern Africa, 2nd ed.
Livingstone, London.
Wilson, M.L., 1993. Early records of some flora and fauna used by the Khoisan of the Western Cape. Southern African
Field Archeology 2, 67-73.
Ye, Y., et al., 2000. Effects of repeated antidepressant treatment of type 4A phosphodiesterase (PDE4A) in rat brain. J
Neurochem 74, 1257–1262.
Zhao, Y., et al., 2010. Review of total synthesis of mesembrine. Youji Huaxue 30 (1), 47–59.
Zwicky, E., 1913. Über Channa, ein Genussmittel der Hottentotten. Vierteljahrsschr. Naturforsch. Gesell. Zürich 58, 371-430.
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