IngredientsMesembrine is a naturally occurring alkaloid isolated from Sceletium tortuosum (also known as kanna), a South African succulent traditionally used for mood elevation and stress relief. The plant grows in the semi-arid Karoo and Namaqualand regions of South Africa. The plant belongs to the family Mesembryanthemaceae and carries the botanical synonym Mesembryanthemum tortuosum L.; Mesembryanthemum tortuosum is a botanical synonym for Sceletium tortuosum.
Sceletium tortuosum (L.) N.E.Br (Mesembryanthemaceae), a succulent sub-shrub endemic to South Africa, is highly valued for its traditional uses as a masticatory and medicine. M. tortuosum contains about 1–1.5% total alkaloids.
Mesembrine is an alkaloid with the molecular formula C17H23NO3 and a molecular weight of 289.37 g/mol. Its IUPAC name is (3aS,7aR)-3a-(3,4-dimethoxyphenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindol-6-one and its CAS number is 468-53-1. The naturally predominant enantiomer, (−)-mesembrine, carries CAS number 24880-43-1 and is also known by the synonyms mesembranone and (–)-mesembrine.
The molecular formula for "mesembrin" was reassigned as C17H23NO3 and is presently known as mesembrine, with the structure deduced as N-methyl-3a-(3′,4′-dimethoxyphenyl)-6-oxo-cis-octahydroindole, which provided the foundation for continued studies on this group of alkaloids.
Mesembrine is the defining member of the mesembrine-type alkaloid class, the dominant phytochemical group in Sceletium tortuosum. 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. The four active alkaloids most frequently quantified by HPLC are mesembrenone, mesembrenol, mesembranol, and mesembrine.
It is reported that mesembrine is virtually the only alkaloid present in the leaves of the species Sceletium tortuosum. However, qualitative differences in the alkaloid profiles were observed between and within different populations of S. tortuosum, as well as among the investigated commercial products. Mesembrine was identified as the main alkaloid constituent in most of the commercial products analysed.
Studies of fermentation processes revealed that mesembrine transforms into mesembrenone when exposed to sunlight and aqueous conditions, while remaining stable in methanol or darkness. 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.
The parent plant is commonly known as kanna or kougoed. The name kanna means "eland" in the click language of the San, carrying a symbolic reference to this large antelope as the "trance animal" called upon during religious and spiritual gatherings; kougoed is Afrikaans for "something to chew."
Extracts of the plant are accessible in raw powdered plant material, tablets, and capsules, which are frequently traded over the internet; individuals use it to improve their sense of well-being and reduce stress. Modern standardized commercial extracts — the most studied being Zembrin® — are manufactured as spray-dried hydroethanolic extracts. The active ingredient of Zembrin is a standardized and characterized aqueous ethanolic (purified water 30% V/V and ethanol 70% V/V, spray-dried onto a maltodextrin carrier) extract of the above-ground material of a cultivated traditionally used selection of the South African plant S. tortuosum.
Hans Zwicky (1914) was the first to report the presence of alkaloids in Sceletium tortuosum, identifying mesembrine and mesembrenine, though their chemical structures were later corrected. Further studies on S. expansum and S. tortuosum reported by Zwicky in 1914 yielded a non-crystalline alkaloid which was named "mesembrin" with the reported molecular formula C16H19NO4. Rimington and Roets reinvestigated this plant in 1937, and attempts to crystallize the alkaloid as a free base or hydrochloride salt were unsuccessful. Bodendorf and Krieger, in their work in 1957, revisited the molecule and successfully crystallized the mesembrine base to its hydrochloride salt, and the structure of mesembrine was reported as N-methyl-3a-(3′,4′-dimethoxyphenyl)-6-oxo-cis-octahydroindole.
Despite a long history of medicinal use and research investigation, there has been a renewed interest in the pharmacological properties of the mesembrine alkaloids and much of the pharmacology has only recently been published. The two major active alkaloids mesembrine and mesembrenone are still in the process of being more fully characterized pharmacologically.
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.
Sceletium tortuosum, known locally as kanna or kougoed, has been utilized by the indigenous Khoisan peoples of southern Africa, including the San (Bushmen) hunter-gatherers and Khoikhoi (Hottentots) pastoralists, for millennia in various social, medicinal, and spiritual contexts. These communities traditionally chewed the fresh or dried leaves and stems of the plant to induce euphoria, alleviate stress, and suppress hunger and thirst, particularly during long hunts or periods of scarcity in arid environments like the Kalahari Desert.
The plant, known as kanna or kougoed, 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.
Indigenous healers of the San and Khoikhoi tribes fermented the plant into kougoed, meaning "chewable thing" in Afrikaans. This preparation was chewed, smoked, or inhaled as snuff to induce relaxation, euphoria, and mental clarity.
In addition to its common use as a masticatory and as a tea, the aerial parts of Sceletium tortuosum were also used for medicinal purposes, especially for gastrointestinal ailments and respiratory conditions. Dried Sceletium tortuosum leaves are used by the San to treat colic in infants, to improve bowel regularity, and to treat abdominal cramps.
Interestingly, Sceletium tortuosum has been used by traditional healers to combat addictions and to wean alcoholics off alcohol.
Written historical accounts dating back to 1685 confirmed that Sceletium tortuosum had been widely used by the San, and their relatives the Khoikhoi, and was subsequently traded with European settlers. Early ethnographic accounts from the 17th century, such as those by Simon van der Stel in 1685, document the Namaqua people — related to the Khoikhoi — gathering and chewing the plant throughout the day for these effects, highlighting its role in daily survival and well-being.
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 — a medicinal root already valued across Asia. The plant has a long history of traditional use by San and Khoikhoi people as a masticatory and medicine, and later by colonial farmers as a psychotropic in tincture form (Pappe, 1868).
The mesembrine-type alkaloid family contains four major quantified compounds. The standardized S. tortuosum extract Zembrin was in the form of a fine dry powder with a dry plant material to extract ratio of 2 to 1, standardized to a total alkaloid content for the four main sceletium alkaloids (mesembrenone, mesembrenol, mesembrine, and mesembranol) of 0.4%.
Chemotype A is represented by samples devoid of mesembrine-type alkaloids, while chemotypes B, C, and E are characterised by high levels of mesembrenol or mesembrine. The "tortuosum"-type Sceletium species contain mesembrine as the major alkaloid along with other minor alkaloids, Δ7mesembrenone, mesembrenone, and mesembranol, and clearly differ from the other species.
Among individual alkaloids:
From a quality-control perspective, most commercially available M. tortuosum products lack standardised extracts such as Zembrin, leading to inconsistent dosage and efficacy. Many of these products contain raw M. tortuosum whole plant powder, resulting in significant batch-to-batch dosage inconsistencies. This can further be attributed to the geographical phytochemical variance of the plant, resulting in variable mesembrine-alkaloid content for each chosen chemovar, as well as the formulation of the product.
Mesembrenol, mesembrine, and mesembrenone can be used as marker compounds for quality monitoring of S. tortuosum raw materials and products.
Mesembrine primarily functions as a selective serotonin reuptake inhibitor (SRI), exhibiting high affinity for the serotonin transporter (SERT) with a Ki value of 1.4 nM, which potently blocks serotonin reuptake at the presynaptic site. This interaction enhances extracellular serotonin levels, contributing to its psychoactive effects. Binding studies indicate that mesembrine interacts at the orthosteric substrate binding site of SERT, consistent with classical SRI mechanisms.
Preclinically, mesembrine has been characterized as a potent serotonin reuptake inhibitor (SRI) with an IC50 of ~1.4 μM for the serotonin transporter (SERT), while showing negligible activity against norepinephrine or dopamine transporters.
In addition to its SRI activity, mesembrine inhibits phosphodiesterase 4B (PDE4B), an enzyme responsible for cAMP hydrolysis, with an IC50 of 7.8 μM. This inhibition elevates intracellular cyclic adenosine monophosphate (cAMP) levels, potentially amplifying downstream signaling pathways involved in mood regulation and neuroprotection.
Mesembrine and synthetic analogues were shown to inhibit phosphodiesterase 4 (PDE4) activity. Mesembrine itself was a very weak PDE4 inhibitor (IC50 29 μM), but some synthetic analogues were considerably more active, with IC50s of 0.1–1 μM. It is mesembrenone, rather than mesembrine itself, that carries the most potent PDE4 inhibitory activity among the naturally occurring alkaloids.
Enzymes in the PDE4 family are particularly important in neuropsychopharmacology. PDE4 hydrolyzes cyclic AMP formed by stimulation of beta adrenergic receptor-linked adenylyl cyclase in brain cortical slices. Rolipram or other selective inhibitors of PDE4 have antidepressant activity in both preclinical and clinical tests and produce memory-enhancing effects in animal models.
The combination of dual PDE4 and 5-HT reuptake inhibition has been argued to have synergistic potential in the treatment of anxiety and depression, with the added value that lower doses can be used to reduce side effects.
Research into high-mesembrine extracts has revealed an additional mechanism beyond classical reuptake inhibition. Kanna inhibits serotonin reuptake by downregulating the serotonin transporter (SERT) and also promotes monoamine release by upregulating vesicular monoamine transporter-2 (VMAT2). It also shows mild inhibition of acetylcholinesterase (AChE) and monoamine oxidase-A (MAO-A).
Kanna inhibits serotonin reuptake by downregulating the serotonin transporter (SERT) and also promotes monoamine release by upregulating vesicular monoamine transporter-2 (VMAT2). It shows mild inhibition of acetylcholinesterase (AChE) and monoamine oxidase-A (MAO-A). The primary mechanism of kanna's mood effects appears to be monoamine release, with serotonin reuptake inhibition as a secondary action.
Other mechanisms which may similarly result in the anxiolytic or antidepressant effect ascribed to Sceletium, such as monoamine release, had not been initially investigated. A subsequent study investigated simultaneously the effect of high-mesembrine Sceletium extract on both monoamine release and serotonin reuptake into human astrocytes and mouse hippocampal neurons, as well as potential inhibitory effects on relevant enzyme activities.
The plant exhibits multiple pharmacological activities, including as a phosphodiesterase-4 inhibitor (PDE4), acetylcholinesterase inhibitor (AChE), CB1 receptor blocker, and CYP17A1 inhibitor.
Mesembrine has analgesic effects in the hot plate test when administered at a dose of 20 mg/kg but does not induce a preference in the conditioned place preference test (CPP). The absence of conditioned place preference is notable from a dependence-risk standpoint, suggesting the compound does not produce rewarding properties in this preclinical model.
Pharmacological fMRI study (Terburg et al., 2013 — Neuropsychopharmacology): In a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry, using a double-blind, placebo-controlled, cross-over design in 16 healthy participants, the dual 5-HT reuptake and PDE4 inhibitor Zembrin was shown to reduce amygdala reactivity to unattended facial fear and also decouple amygdala–hypothalamus connectivity. These results support the potential anxiolytic actions of Zembrin and provide a foundation for exploring the clinical potential of dual PDE4 and 5-HT reuptake inhibitors for the treatment of anxiety disorders and depression. This was an acute single-dose study; its small sample and healthy volunteer population are notable limitations.
Behavioral studies (Reay et al., 2020 — Human Psychopharmacology): Results of the current studies provide the first tentative behavioral evidence to support the anxiolytic properties of Sceletium tortuosum (25 mg Zembrin®) but fail to replicate the previously reported enhancement of cognitive function. The study objective was to investigate the anxiolytic properties of a standardized extract of Sceletium tortuosum (Zembrin®). By this point, a small body of evidence had accumulated to support its safety, cognitive enhancing, and anxiolytic properties.
Systematic review: Although S. tortuosum-derived products offer valuable insights, such as a favourable safety profile and potential efficacy as an anxiolytic and antidepressant, several limitations have been identified, including small sample sizes and studies conducted in clinically irrelevant populations. Limited data shows no statistically significant effect on reducing anxiety symptoms. Clinical data are currently insufficient to support the use of kanna for any specific medical indication.
Overall, evidence for anxiolytic effects at the neural-circuit level (fMRI) is promising, and behavioral studies provide tentative corroboration, but the body of clinical evidence remains preliminary: studies are few, small, restricted to healthy volunteers, and of short duration.
The antidepressant and anxiolytic clinical effects of S. tortuosum have been found both in case reports and more recently, double-blind studies. A small series of case reports described preliminary evidence for antidepressant and anxiolytic activity in patients suffering from major depression who were treated with tablets of milled S. tortuosum.
Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. However, to date, there have not been any large or long-term studies or studies in specific diseases. No large-scale randomized controlled trials in clinically depressed populations have been published; existing antidepressant evidence therefore remains mechanistically plausible but clinically unverified.
Crossover RCT (Chiu et al., 2014): 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. 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 found. Zembrin was well tolerated.
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.
RCT in physically active adults (Hoffman et al., 2020): In a randomized placebo-controlled trial of 60 physically active men and women aged 20–35, Sceletium tortuosum extract (Zembrin) treatment (25 mg, once daily, orally) for eight days significantly improved complex reactive performance (requiring responses to repeated visual stimuli with a cognitive load) compared with placebo. The extract was also associated with significantly higher reactive agility compared to placebo in a task that required decision making. However, no significant differences 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.
Notably, the 2020 Reay et al. study failed to replicate the cognitive enhancements observed by Chiu et al. (2014), highlighting the inconsistency that may stem from differences in study design, population, and cognitive battery used.
In the 3-week crossover RCT, Zembrin treatment did not significantly affect the composite score of the 9 cognitive tests or depression scores (measured by HAM-D). Subjects taking Zembrin reported improvement in the subjective quality of sleep (on the HAM-D subscale) and a positive effect on onset of sleep compared with the placebo group. Improvements in mood and sleep quality represent some of the more consistently reported subjective findings across small clinical studies.
The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities — including antimalarial, antioxidant, immunomodulatory, anti-HIV, and neuroprotection — in in vitro or in vivo studies. These activities have not been evaluated in human clinical trials, and their clinical relevance remains entirely speculative at this stage.
Bennett and colleagues reported that S. tortuosum showed potent anti-inflammatory capacity in the context of chronic disease, though this finding is derived from preclinical work and requires human confirmation.
Based on mechanistic and clinical research, mesembrine and Sceletium tortuosum alkaloids are associated with the following body systems:
Clinical studies evaluating potential CNS effects have used 25 mg (either as a single dose or once daily, with treatment durations ranging from 8 days to 9 weeks) of a proprietary extract of S. tortuosum (standardized to a total alkaloid content for the 4 main Sceletium alkaloids [mesembrenone, mesembrenol, mesembrine, and mesembranol] of 0.4%).
A safety and tolerability study 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.
A daily dose of 2–12 mg of total alkaloids from M. tortuosum is recommended by the African Herbal Pharmacopoeia; however, clinical studies investigating Zembrin® have typically used much lower doses. These studies commonly administered 1–2 tablets (25 or 50 mg Zembrin®) as a single or daily dose, delivering 0.35–0.45% total alkaloids of the specified four markers.
The standardized Zembrin® extract is described as a 2:1 extract (meaning 2 g plant material per 1 g extract). Each active opaque white size-1 hardshell gelatin capsule contained 25 mg of Zembrin together with inert excipients, equivalent to 50 mg of dry raw above-ground S. tortuosum.
Published clinical evidence is lacking to provide definitive dosing recommendations. No dose-finding study in clinical populations has been completed, and there is no established therapeutic dose for any condition.
The objective of the 3-month safety study was to evaluate the safety and tolerability of two doses (8 mg and 25 mg once daily) of a 2:1 standardized extract of Sceletium tortuosum, trademarked Zembrin®, in healthy adult volunteers. This was a randomized, double-blind, parallel-group, placebo-controlled single-center study. Zembrin® was also well tolerated by healthy human subjects when provided once daily for 3 months at 8 mg and 25 mg dosages.
Zembrin is generally well-tolerated and adverse event incidence is typically lower than placebo in reported trials. However, all safety data to date come from small, short-term studies in healthy volunteers.
The purpose of the genotoxicity assessment was to report on the genotoxic safety of Zembrin® by describing its effects in a set of three genotoxicity tests according to OECD guidelines and under Good Laboratory Practice. Genotoxic safety was evaluated performing three standard genotoxicity tests according to OECD guidelines 471, 487, and 474. Based on the outcome of the three genotoxicity tests, it was concluded that Zembrin® is not of genotoxic concern.
In acute oral toxicity tests, the maximum tolerable dose was more than 10.0 g/kg body weight in SD rats and ICR mice, and showed no toxicological signs during the period of the study. A 14-day repeated oral toxicity study was conducted at 0, 250, 750, 2500, and 5000 mg/kg bw/day, and a 90-day subchronic repeated oral toxicity study was conducted at 0, 100, 300, 450, and 600 mg/kg bw/day. No in vitro mutagenic or clastogenic activity was observed in the presence or absence of metabolic activation up to the maximum OECD-recommended test concentrations. No genotoxicity was observed in the mammalian micronucleus study up to the highest dose tested of 700 mg/kg bw.
This is the most clinically significant safety concern identified in the literature. Mesembrine-alkaloids act as SSRIs; therefore, when used in combination with other serotonergic or MAO-inhibiting drugs, they can potentially cause serious unwanted conditions such as serotonin syndrome, a potentially toxic state characterised by excessive serotonergic activity, causing confusion, agitation, hypertension, hyperthermia, and tachycardia.
The combination of MAO inhibitors and serotonergic drugs poses the highest risk of life-threatening serotonin toxicity. Mesembrine alkaloids, acting as SSRI and PDE4 inhibitors, may cause herb–drug interactions leading to serious adverse events such as serotonin syndrome when combined with serotonergic or MAO-inhibiting drugs.
From a quality-control perspective, most commercially available M. tortuosum products lack standardised extracts such as Zembrin, leading to inconsistent dosage and efficacy, as well as the potential for experiencing severe adverse events for users. Many of these products contain raw M. tortuosum whole plant powder, resulting in significant batch-to-batch dosage inconsistencies.
Therefore, determining a safe yet therapeutically effective dose of M. tortuosum, based on its alkaloid content, is critical. A daily dose of 2–12 mg of total alkaloids from M. tortuosum is recommended by the African Herbal Pharmacopoeia.
While the plant has been studied in clinical populations, this has only been in healthy subjects. To date, there have not been any large or long-term studies or studies in specific diseases. No studies have tested the effects of S. tortuosum on aging-related diseases that are not associated with the central nervous system. Research on S. tortuosum faces several gaps. Existing studies utilize diverse extraction methods, hindering comparisons. Furthermore, crucial areas like toxicology, clinical trials, and bioavailability studies remain underexplored.
Health conditions that Mesembrine may help support.
Body systems that Mesembrine may help support.
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