kanna

Kanna (Sceletium tortuosum): A Comprehensive Reference

1. Identity, Botanical Classification, and Common Forms

Botanical names and taxonomy. Kanna is formally known as Mesembryanthemum tortuosum, and is often referred to by its long-standing synonym Sceletium tortuosum (L.) N.E.Br. It is a succulent plant in the family Aizoaceae, native to the Cape Provinces of South Africa. In English it is commonly known as kanna — a name derived from the plant's local Khoekhoe name — or alternatively kougoed, an Afrikaans term meaning "chewable thing," originally referring to a fermented preparation of the plant chewed by the indigenous Khoisan peoples for its medical and psychoactive effects. Other recorded common names include channa, kauwgoed, and kougoed. The genus Sceletium belongs to the family Aizoaceae and subfamily Mesembryanthemoideae, recognized in 1925 by N.E. Brown.

Natural distribution. Sceletium tortuosum is a little succulent plant that grows in the semi-arid Karoo and Namaqualand regions of South Africa. Belonging to the genus Sceletium in the family Aizoaceae, it grows in the southwestern region of South Africa, primarily in the Northern Cape, Western Cape, and Eastern Cape Provinces. It was once plentiful in Namaqualand in the Northern Cape Province, and the lands in that area were named "Kougoedvlakte," which translates into "Chewing Stuff Plains." In the Western Cape Province, the plants were also so abundant that the district of Kannaland was founded there, as "the land of Kanna."

Species within the genus. There are approximately nine species within the genus Sceletium, but tortuosum has been the primary focus of both traditional use and modern research.

Common forms and preparations. Traditional preparation involves crushing the plant material, placing it in a bag to ferment, then drying it in the sun. The dried plant material can be chewed, smoked, or made into powder and used as snuff. The plant material has also been prepared as a tincture or tea, or eaten raw. In modern commerce, extracts of the plant are accessible in raw powdered plant material, tablets, and capsules, which are frequently traded over the internet. Various forms of the plant are also sold as tea bags, often mixed with Red Bush Tea (Aspalathus linearis) or Honeybush tea (Cyclopia spp.), purchased in South African supermarkets. Standardized commercial extracts, most notably Zembrin®, are produced for use as dietary supplement ingredients in functional foods and capsules.

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2. Traditional and Historical Use

Indigenous peoples and pre-European use. The plant has likely been used by South African pastoralists and hunter-gatherers for thousands of years. Plants of the genus Sceletium have likely been used for millennia by San and Khoi peoples as masticatories and traditional medicines for thirst, hunger, fatigue, and social and spiritual purposes; this knowledge from oral tradition of how it was used has declined over the past three centuries due to colonization, conflict, and cultural disruption.

The San and Khoikhoi peoples. The plant, known as kanna or kougoed by the San and Khoikhoi people, was mainly chewed or smoked to stay alert and suppress appetite during long hunts. The San were traditionally hunter-gatherers, while the Khoikhoi were pastoralists who herded livestock. The name kanna (meaning "eland" in the click language of the San) has a symbolic reference to this large antelope, as the "trance animal," which was called upon during religious and spiritual gatherings. Kougoed is Afrikaans for "something to chew."

First written accounts and European contact. The first known written account of the plant's use, referred to as Kanna, was in 1662 by Jan van Riebeeck. Its use substantially predates European contact and is recorded in writing from the late seventeenth century onward, with Dutch East India Company (VOC) records from 1685 and later providing some of the earliest written references. The written history of kanna in European accounts begins in 1610, with the logs of a Dutch ship called The Globe, docking in what is now Saldanha Bay near Cape Town. The ship's crew documented their search for a local root called "kanna," comparing it favorably to ginseng.

Purposes of traditional use. The Khoisan used kanna for a wide range of purposes: historically, the plant was used by native San hunter-gatherers and Khoi people to quench their thirst, fight fatigue, and for healing, social, and spiritual purposes. The plant is traditionally known for its ability to elevate mood, reduce stress, tension, anti-anxiety, and its tranquilizing properties. Furthermore, it is used for illnesses such as abdominal pains, toothache, and some people chew, smoke, or use it as tea or snuff mostly for pressure. Its long history of use in South Africa includes enhancing sociability, elevating mood, improving general well-being, improving memory, treating alcoholism, improving endurance, reducing fatigue, relieving anxiety and depression, promoting calmness, improving insomnia, quenching thirst and hunger, relieving pain (e.g., headache, toothache), reducing nausea, and ameliorating colic. Along with dagga, kanna constituted an important element in southern Africa's precolonial exchange economy.

Traditional fermentation process. The Khoisan traditional preparation involved harvesting the leaves and stems, then crushing the plant material and placing it inside an animal skin or fabric to ferment over several days. A local informant from the Namaqualand area, as cited in phytochemical research, described the traditional process: the fermentation of kanna results in lowering oxalic acid, lowering 4′-O-demethylmesembrenol, and significantly converting mesembrine to mesembrenone and Δ7-mesembrenone. The traditional method involves leaving a bag of crushed kougoed in the sun to warm, allowing the plant to "sweat." After 2 to 3 days the bag is opened, the kougoed is mixed and re-sealed; on the eighth day after crushing, the bag is opened and the kougoed spread out to dry in the sun. According to historical records, farmers in the Cape also used S. tortuosum as a decoction or tincture and as a sedative. The narcotic effect is claimed to be much more pronounced after fermentation. Ethnohistorical testimonies also suggest widespread use of honey-alcohol combined with plant material for psychotropic and medicinal purposes, including kanna, which produced a "spiked" honey drink known as khadi.

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3. Key Constituents and Active Compounds

3.1 Alkaloid Profile

To date, more than 25 alkaloids from four main structural classes — mesembrine, Sceletium A4, joubertiamine, and tortuosamine — have been identified in Sceletium species, with mesembrine-types predominating. Recent advances include the structural characterization of new alkaloids such as channaine and sceletorines A and B, with evidence indicating sceletorine B may be a biosynthetic precursor to channaine. These discoveries deepen understanding of the chemical diversity and transformation of alkaloids in Sceletium tortuosum, which are key to its pharmacological properties.

Mesembrine-type alkaloids, which include mesembrenone, mesembrine, mesembranol, and mesembrenol, are recognized as the major chemotaxonomic markers of the plant, and they account for its psychoactive properties. The plant contains about 1–1.5% total alkaloids.

Mesembrine. Mesembrine, a phenylethylamine alkaloid, was first extracted from S. tortuosum in 1898. It is the major alkaloid found in S. tortuosum, occurring at levels of 0.3% in the leaves and 0.86% in the stems. The amount of active compounds in the plant appears to vary by season and locality. Mesembrine is the major psychoactive compound in S. tortuosum and is a potent selective serotonin (5-HT) reuptake inhibitor. At much higher concentrations, mesembrine has demonstrated limited inhibition of noradrenaline and dopamine uptake.

Mesembrenone. Mesembrenone is of particular pharmacological interest because it acts on two distinct targets. Mesembrenone is both a potent 5-HT transporter inhibitor and a PDE4 inhibitor. Zembrin® contains much lower levels of mesembrine (13.3%) but is more prominent with regard to mesembrenone (47.9%), possibly affording it more pronounced effects on mood, cognition, and well-being.

Other alkaloids and alkaloid ratios. Zembrin®, the most extensively studied commercial extract, is a well-characterized standardized hydroethanolic extract of a cultivated variety of Sceletium tortuosum and is standardized to contain 0.35–0.45% total alkaloids (mesembrenone and mesembrenol ≥60%, and mesembrine <20%). The pharmacological profile of any given extract of S. tortuosum will show variable pharmacological properties in accordance with its specific chemotype — that is, the alkaloid content and relative alkaloid composition of the extract. The high-mesembrine extract Trimesemine™ (>70% mesembrine) is more potently antioxidant and anti-inflammatory in action, while, as noted, Zembrin® is richer in mesembrenone.

3.2 Effect of Fermentation on Alkaloid Chemistry

Research has suggested that the essential step in the production of kougoed may not be entirely due to "fermentation" per se but that crushing the plant material and the consequent mixing of cellular material may also be equally necessary. Based on experimental results, simply crushing and drying at 80 °C may be a quick alternative method to modify the alkaloid content. Such treatments appear to have a rational pharmacological basis which is considered to have evolved over many generations by continued experimentation by the indigenous people of southern Africa.

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4. Established Mechanisms of Action

4.1 Serotonin Reuptake Inhibition (SERT)

A standardized ethanolic extract (Zembrin®) was tested along with purified alkaloids mesembrine, mesembrenone, and mesembrenol on a panel of receptors, enzymes and other drug targets. The extract was a potent blocker in 5-HT transporter binding assays (IC₅₀ 4.3 μg/ml) and had powerful inhibitory effects on phosphodiesterase 4 (PDE4) (IC₅₀ 8.5 μg/ml), but not other phosphodiesterases. Mesembrine was the most active alkaloid against the 5-HT transporter (K_i 1.4 nM), while mesembrenone was active against both the 5-HT transporter and PDE4 (IC₅₀'s <1 μM).

Kanna inhibits serotonin reuptake by downregulating the serotonin transporter (SERT) and also promotes monoamine release by upregulating vesicular monoamine transporter-2 (VMAT2). The primary mechanism of kanna's mood effects appears to be monoamine release, with serotonin reuptake inhibition as a secondary action.

4.2 Phosphodiesterase-4 (PDE4) Inhibition

The psychoactive effects of mesembrine-type alkaloids and their capabilities in treating different CNS disorders have been attributed to their ability to act as phosphodiesterase-4 (PDE4) and serotonin reuptake inhibitors (SRIs), which are responsible for regulating intracellular messengers and synaptic and neuronal serotonin levels, respectively. Mesembrine hydrochloride is an inhibitor of phosphodiesterase type 4 (PDE4) at a half maximal inhibitory concentration of 29 μM. The selective inhibition of the PDE4 family of enzymes affects cell signaling. PDE4 inhibitors are used for the treatment of inflammatory diseases including asthma, chronic obstructive pulmonary disease, and psoriasis, as well as for the treatment of anxiety and depression. Evidence suggests that PDE4 inhibitors also have a crucial role in regulating cognition via the PDE4–cyclic adenosine monophosphate cascade.

4.3 Acetylcholinesterase (AChE) Inhibition

In an assay of a methanol extract of S. tortuosum, both fermented and unfermented alkaloids had a similar ability to inhibit acetylcholinesterase, a cholinesterase enzyme that terminates nerve impulse transmission in the CNS, demonstrating greater activity than mesembrine alone and suggesting that other alkaloids contribute to the acetylcholinesterase-inhibiting ability of S. tortuosum.

4.4 CB1 Receptor Blockade

The alkaloids in S. tortuosum may block cannabinoid type 1 (CB1) receptors, which are key in inhibiting adenylate cyclase activity, regulating ion channel activities, and activating the mitogen-activated protein kinase cascade. CB1 receptors are found in close proximity to 5-HT transporters and mediate their release. In a CB1 binding assay, combinations of the fermented alkaloid extract and the synergistic activity of the combined alkaloids resulted in greater activity.

4.5 CYP17A1 Inhibition and Glucocorticoid Synthesis

High levels of mesembrine extracted from S. tortuosum displayed potential cytoprotective and mild anti-inflammatory properties in the setting of acute inflammation in the peripheral compartment. In addition, it has been shown to target specific enzymes in the adrenal cortical steroid synthesis pathway and reduce glucocorticoid synthesis. In terms of diabetes and obesity, this is significant since the etiology of both conditions is linked to chronically elevated pro-inflammatory cytokine and glucocorticoid levels.

In summary, S. tortuosum exhibits multiple pharmacological activities, including as a phosphodiesterase-4 inhibitor (PDE4), acetylcholinesterase inhibitor (AChE), CB1 receptor blocker, and CYP17A1 inhibitor.

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5. Scientific Evidence by Area of Use

5.1 Anxiety and Stress

fMRI neuroimaging study (Terburg et al., 2013). Researchers tested the acute effects of Zembrin® administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, crossover design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin®. Follow-up connectivity analysis on the emotion-matching task showed that amygdala–hypothalamus coupling was also reduced. These results demonstrated, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provided supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.

Behavioral anxiety study (Reay et al., 2020). Two placebo-controlled, double-blind, between-subject studies investigated the effects of a single dose of Sceletium tortuosum (25 mg, Zembrin®) on laboratory stress/anxiety responding in 20 young healthy volunteers. To elicit feelings of stress/anxiety, participants completed 20 minutes of the multitasking framework in study 1 and a 5-minute simulated public speaking task in study 2. Results showed no treatment effect in study 1; however, study 2 revealed subjective anxiety levels to be significantly lower in the Zembrin® group at the prestress induction point and a significant interaction between treatment and time on heart rate. Taken together, results indicated that a single dose of Zembrin® can ameliorate laboratory stress/anxiety responding in healthy volunteers. This provided the first tentative behavioral evidence to support the anxiolytic properties of Sceletium tortuosum (25 mg Zembrin®).

Evidence strength for anxiety: The evidence for anxiolytic effects is preliminary. It rests on a small fMRI study (n=16) and two behavioral experiments (n=20 each) in healthy volunteers, using single doses of a standardized proprietary extract. Results are mixed across studies, and no studies have assessed clinical anxiety disorder populations.

5.2 Cognitive Function

Pilot randomized controlled trial in middle-aged adults (Chiu et al., 2014). In a randomized placebo-controlled crossover trial of 21 cognitively healthy people aged 45–65, S. tortuosum treatment (Zembrin; 25 mg capsule once daily; manufactured according to EU GMP) for 3 weeks improved cognitive set flexibility (p<0.032; Cohen's d effect size=1.47) and executive function. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P < 0.032) and executive function (P < 0.022), compared with the placebo group. Positive changes in mood and sleep were also found. Zembrin was well tolerated. The researchers noted that the promising cognitive enhancing effects of Zembrin likely implicate the PDE-4–cAMP–CREB cascade, a novel drug target in the potential treatment of early Alzheimer's dementia.

Randomized controlled trial in young active adults (Hoffman et al., 2020). In a randomized controlled trial of 60 physically active men and women aged 20–35 (who exercised at least 2 days per week), S. tortuosum extract treatment (25 mg/day, orally; Zembrin®, PLT Health Solutions) for 8 days significantly improved complex reactive performance.

Null findings. No significant differences between Sceletium tortuosum extract and placebo groups were observed for visual tracking performance, motor reaction time, visual reaction time, physical reaction time, anxiety, depression, anger/hostility, vigor, confusion, subjective feelings of alertness, or subjective energy. Based on the limited available evidence from clinical trials, it is possible that Sceletium tortuosum may improve cognitive functions with high complexity or stress/load without affecting simpler cognitive tasks.

Evidence strength for cognition: No clinical trials have tested whether Sceletium tortuosum can prevent dementia or age-related cognitive decline. Only two studies have tested the effects of Sceletium tortuosum on cognitive functions, one in young adults and the other in middle-aged adults; no studies have tested Sceletium tortuosum in older adults with cognitive symptoms. Evidence is preliminary, coming from small, short-duration trials in healthy populations only.

5.3 Mood and Depression

The antidepressant and anxiolytic clinical effects of S. tortuosum have been found both in case reports and more recently double-blind studies. The mechanisms of serotonin reuptake inhibition and PDE4 inhibition are pharmacologically analogous to known antidepressant drug classes, and the activity of the Sceletium tortuosum extract on the 5-HT transporter and PDE4 may explain the clinical effects of preparations made from this plant, with these activities relating particularly to the presence of mesembrine and mesembrenone. However, this plant has not yet been studied in a clinical population for depression, though it has potential for managing anxiety and depression.

Evidence strength for mood/depression: Evidence consists primarily of in vitro and animal pharmacology establishing plausible mechanisms, supported by a small number of human studies in non-clinical populations. There are no randomized controlled trials in populations diagnosed with depressive disorders. The evidence base remains insufficient to draw clinical conclusions.

5.4 Anti-inflammatory and Antioxidant Effects

In an in vitro study using human astrocytes, the high-mesembrine Sceletium extract exerted cytoprotective and anti-inflammatory effects. In contrast, the high delta7-mesembrenone extract, rich in polyphenols, exhibited a potent antioxidant effect, although with relatively higher risk of adverse effects at overdose levels. Both extracts were concluded to potentially be employed as either a preventative supplement or complementary treatment in the context of obesity and diabetes. The results showed that the high mesembrine extract demonstrated anti-inflammatory and cytoprotective effects, while the polyphenols-rich delta7-mesembrenone extract showed potent antioxidant activity. Both extracts showed mild neuroprotective effects as indicated by inhibition of acetylcholinesterase and tyrosinase enzymes.

Evidence strength for anti-inflammatory/antioxidant effects: Evidence is based entirely on in vitro cell-culture experiments. No human clinical trials have tested these endpoints. All findings in this domain must be considered preclinical only.

5.5 Appetite Suppression

The leaf is also chewed to relieve toothache and abdominal pain, and as a hunger and thirst suppressant during hunting trips. This appetite-suppressing effect has a deep ethnobotanical basis but remains without formal clinical evaluation. No controlled human trials specifically examining appetite suppression have been published.

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6. Body Systems and Health Areas Associated with Kanna

• Central nervous system (CNS) / mood regulation: Primary area of scientific interest; SERT inhibition and PDE4 inhibition both directly modulate neurotransmitter signaling relevant to mood, anxiety, and depression.
• Stress response / hypothalamic-pituitary-adrenal (HPA) axis: A high-mesembrine Sceletium tortuosum extract was shown to possess cytoprotective and mild anti-inflammatory properties in monocytes and to target specific P450 enzymes to reduce adrenal glucocorticoid synthesis. This is significant since the etiology of both obesity and diabetes is linked to inflammation and excess glucocorticoid production.
• Cognition and memory: Via the PDE4–cAMP–CREB cascade, S. tortuosum has been proposed to support cognitive flexibility and executive function; PDE-4D knockout mice show enhanced memory function mediated through hippocampal neurogenesis via phosphorylated cAMP response element binding protein (pCREB) signaling.
• Inflammation / immune system: In vitro evidence for anti-inflammatory and immunomodulatory properties, primarily through AChE inhibition and cytokine modulation in astrocytes; no clinical evidence.
• Gastrointestinal / appetite: Traditional use for abdominal pain, hunger suppression, and thirst; no modern clinical evidence.
• Nociception / pain: Traditional use as a mild analgesic for toothache and headache; no clinical trial data.

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7. Dosage Forms and Reported Dosages

Zembrin® is a standardized water and ethanol extract of Sceletium tortuosum that contains a total alkaloid content (mesembrenone, mesembrenol, mesembranol, and mesembrine) of around 0.4%. The most commonly tested Zembrin® dose is 25 mg, daily, orally, which is equivalent to 50 mg of dry raw Sceletium tortuosum.

Nell, Siebert, Chellan, and Gericke (2013) demonstrated that both a low (8 mg) and a higher (25 mg) daily dose of Zembrin® ingested for 3 months were well tolerated in healthy participants. The anxiolytic study by Reay et al. (2020) used a single dose of 25 mg, Zembrin®, in a placebo-controlled, double-blind design with 20 young healthy volunteers.

Published clinical evidence is lacking to provide formal dosing recommendations.

In terms of preclinical toxicology dose escalation: the 14-day study tested Zembrin® doses of 250, 750, 2500, and 5000 mg/kg/day by oral gavage. The 90-day subchronic repeated oral toxicity study tested Zembrin® doses of 100, 300, 450, and 600 mg/kg/day by oral gavage.

Regarding the extrapolated acceptable daily intake: the NOAEL of the 90-day repeated dose oral toxicity study was 600 mg/kg bw/day — the highest dose tested — and applying a 100× safety factor to a 70 kg person results in an estimated acceptable daily intake (ADI) of 420 mg. It should be emphasized that this figure is an extrapolation from rodent toxicology data and does not constitute a clinical dosing recommendation.

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8. Safety Considerations and Interactions

8.1 Preclinical Toxicological Studies

In male and female Crl:(WI)BR Wistar rats, Zembrin® showed no mortality or treatment-related adverse effects spanning 14 or 90 days with doses of 600 mg/kg bw/day and 5,000 mg/kg bw/day, respectively. No mortality occurred in either study, and no target organs or treatment-related toxicological effects were identified. The NOAEL of the 14-day repeated dose oral toxicity study was 5,000 mg/kg bw/day — the highest dose tested.

8.2 Clinical Safety Evidence

Zembrin® is generally well-tolerated and adverse event incidence is typically lower than placebo across published trials. Zembrin® was also well tolerated by healthy human subjects when provided once daily for 3 months at 8 mg and 25 mg dosages. No severe adverse effects were reported in these studies, and the extract could be considered a safe therapeutic agent on the basis of available data. To date, there have not been any large or long-term studies or studies in specific diseases.

8.3 Drug Interactions

There are no reports to date of herb-drug interactions with Sceletium tortuosum. However, based on its mechanisms of action, it should not be used with drugs known to alter serotonin uptake or release, including the antidepressants SSRIs and SNRIs. Another drug that may interact with Sceletium tortuosum based on its inhibitory action towards phosphodiesterase 4 is roflumilast, approved in the US and EU for treating severe chronic obstructive pulmonary disease.

Commercial availability of complementary medicines often sees herbal preparations being used without medical supervision, even in combination with prescribed treatments. This poses a serious risk for possible drug interactions and toxicity, such as serotonin syndrome when SSRIs are co-administered with serotonergic botanicals. Because Sceletium can inhibit serotonin reuptake and modulate PDE4, combining it with other serotonergic agents — such as SSRIs, SNRIs, MAO inhibitors, certain migraine medications, or St. John's wort — could theoretically increase the risk of serotonin syndrome or other unpredictable neurochemical effects. While serious cases have not been systematically reported in clinical trials, those trials typically exclude people on such medications.

8.4 Overall Evidence Limitations

A few, small, short-duration clinical trials have suggested that Sceletium tortuosum extracts may improve some complex cognitive functions; however, evidence from large, long-term studies is lacking. Sceletium tortuosum extracts are generally well-tolerated, but long-term safety has not been established. The totality of the clinical evidence derives almost entirely from studies of a single proprietary standardized extract (Zembrin®), predominantly in healthy volunteers. Generalizability to raw plant material, non-standardized extracts, and patient populations with existing conditions remains uncertain. At present, little to no pharmacological information is available in terms of the molecular physiological effects of mesembrine alkaloids in medical clinical settings.

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