Article

A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial of Extract Sceletium tortuosum (Zembrin) in Healthy Adults

Authors:
  • Tiervlei Trial Centre
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Abstract

Objectives: The objective of the 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 the South African medicinal plant Sceletium tortuosum (L.) N.E. Br., trademarked Zembrin,(®) in healthy adult volunteers over a three-month period. Design: This was a randomized, double-blind, parallel-group, placebo-controlled single center study. Setting: Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, Cape Town, South Africa. Participants: The study took place between February 2 and July 27, 2009. Thirty-seven healthy adults were recruited from the general population. Intervention: Participants were randomized to receive either one of two doses of study medication, or an identical placebo, taken once daily for 3 months. Of the 37 subjects, 12, 12, and 13 subjects received 8 mg extract Sceletium tortuosum (Zembrin), 25 mg extract Sceletium tortuosum (Zembrin), and placebo treatment, respectively. Outcome measures: No efficacy variables were assessed. The safety and tolerability variables comprised of vital signs, physical examination, 12-lead electrocardiogram (ECG), laboratory assessments (hematology, biochemistry, and urinalysis), and the recording of adverse events (AEs). Results: There were no apparent differences between the three treatments with regard to vital signs, 12-lead ECG, body weight, and physical examination from screening to the end of the 3-month treatment period. No significant changes were observed in hematology or biochemistry parameters between initial screening and the end of the study. Both doses of extract Sceletium tortuosum (Zembrin) were well-tolerated. The most commonly reported AE was headache, followed by abdominal pain and upper respiratory tract infections, all with greater incidence in the placebo group than in the treatment groups. Unsolicited positive effects on well-being were noted in patient diaries by some participants taking extract Sceletium tortuosum (Zembrin), including improved coping with stress and sleep. Conclusion: Both doses of extract Sceletium tortuosum (Zembrin) (8 mg and 25 mg) were well tolerated when used by healthy human subjects once daily for 3 months.

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... The subjective ratings of generalized well -being and positive mood states in our study [56] agrees well with a recent safety and tolerability study on Zembrin® in healthy subjects who reported "uplifted spirits" and better coping with stress and depressing events [57]. Furthermore, subjects taking Zembrin® reported improvement in the subjective quality of their sleep on the HAM -D subscale: the mean rating of sleep onset at baseline, 0.76 (SD = 1.14), changed to 0.43 (SD =0.93) at week 3 (paired t-test, t = 2.09, df = 20, p=0.049, 2-tailed). ...
... Furthermore, subjects taking Zembrin® reported improvement in the subjective quality of their sleep on the HAM -D subscale: the mean rating of sleep onset at baseline, 0.76 (SD = 1.14), changed to 0.43 (SD =0.93) at week 3 (paired t-test, t = 2.09, df = 20, p=0.049, 2-tailed). In both studies [53,56,57], Zembrin® treated group found an overall improvement in the quality of sleep. ...
... There were no changes in blood pressure, pulse, temperature and weight in either the Zembrin® group or the placebo group. Intriguing enough, the study led by Neil et al. [57] found that the placebo group complained of increased frequency of adverse events than the Zembrin® group. The incidence of treatment emergent adverse events (TEAE) classed as "mild" and "moderate" was quite low ...
Article
Converging evidence suggests that Disrupted in Schizophrenia (DISC-1) is a recognized risk gene for schizophrenia. The interaction of DISC- with PDE-4 (Phosphodiesterase Subtype-4) plays a crucial role in neurodevelopment and neuro-inflammation in schizophrenia. . Serotonin has drawn increased attention for its role in modulating cognition function. Hence dual targeting Selective Serotonin Reuptake site (SSRI) and PDE-4 may offer novel therapeutic paradigm towards augmenting antipsychotics in schizophrenia. Translational studies show that the family of mesembrane-related alkaloids isolated from the South African plant: Sceletium tortuosum have been shown to hit dual targets: SSRI and PDE- 4 allosteric site. The promising findings warrant a proof-of-concept randomized controlled study Zembrin extract in schizophrenia.
... The subjective ratings of generalized well -being and positive mood states in our study [56] agrees well with a recent safety and tolerability study on Zembrin® in healthy subjects who reported "uplifted spirits" and better coping with stress and depressing events [57]. Furthermore, subjects taking Zembrin® reported improvement in the subjective quality of their sleep on the HAM -D subscale: the mean rating of sleep onset at baseline, 0.76 (SD = 1.14), changed to 0.43 (SD =0.93) at week 3 (paired t-test, t = 2.09, df = 20, p=0.049, 2-tailed). ...
... Furthermore, subjects taking Zembrin® reported improvement in the subjective quality of their sleep on the HAM -D subscale: the mean rating of sleep onset at baseline, 0.76 (SD = 1.14), changed to 0.43 (SD =0.93) at week 3 (paired t-test, t = 2.09, df = 20, p=0.049, 2-tailed). In both studies [53,56,57], Zembrin® treated group found an overall improvement in the quality of sleep. ...
... There were no changes in blood pressure, pulse, temperature and weight in either the Zembrin® group or the placebo group. Intriguing enough, the study led by Neil et al. [57] found that the placebo group complained of increased frequency of adverse events than the Zembrin® group. The incidence of treatment emergent adverse events (TEAE) classed as "mild" and "moderate" was quite low ...
... Whether Zembrin behaves similarly towards pulmonary inflammatory cells in vitro and in vivo, remains uncertain. Two clinical studies of Zembrin in normal subjects do not find any adverse effects on the respiratory system (101,103). Mesembrine alkaloids are distinguished from classical PDE-4 inhibitors in displaying concomitant serotonergic activity. ...
... In two controlled clinical studies in healthy control subjects (Zembrin at oral dosage of 25 mg, was safe and well tolerated ( 101,103). In both studies, no changes in blood pressure, pulse, temperature and weight in either the Zembrin group or the placebo group were found. ...
... The incidence of treatment emergent adverse events (TEAE) classed as "mild" and "moderate" was quite low, with no nausea or vomiting. Intriguing enough, the 3month RCT study led by Neil et al (103) found that higher frequency of adverse events occurred in the placebo group. No abnormalities were found in the EKG indices as well as hematological indices, metabolic parameters (lipid, fasting glucose, electrolytes ),liver and kidney functions. ...
Article
Full-text available
Recently with the changing landscape of the aging population and the increase in incidence of Alzheimer’s disease (AD), there has been marked interest to develop strategies to prevent, delay and modify AD. We review the diverse lines of evidence in support of the emerging role of cAMP-mediated Phosphodiesterase (PDE) signalling with respect to aging, inflammation and depression. In view of the link of PDE to Epigenetic complex, targeting PDE through designing modulators and inhibitors of PDE may represent a novel approach in AD therapeutics. We review critically the translational studies of the proprietary Zembrin extract harvested and processed from the South African plant, Sceletium tortuosum, highlighting the dual property of Zembrin in targeting coupling of PDE and serotonin signaling mechanisms in vitro and in vivo models of AD and cognition. The promising clinical findings of Zembrin in cognition suggest that Zembrin extract may merit randomized controlled trials in AD to establish the efficacy and safety in AD.
... In our proof-of-concept randomized placebo-controlled study, we hypothesize that Zembrin enhances cognition in healthy subjects. Previously, a RCT trial reported that daily oral dosage of 25 mg for 3 months was safe and well tolerated [21]. Our study demonstrated for the first time that Zembrin improved executive function and cognitive flexibility in healthy control subjects. ...
... The subjective ratings of generalized well-being and positive mood states in our study agreed well with a recent safety and tolerability study on extract Sceletium tortuosum (Zembrin) in healthy subjects who reported "uplifted spirits" and better coping with stress and depressing events [21]. The baseline HAM-D scores in both groups were <6.0 at the start of the study. ...
... In this study, Zembrin exerted an overall improvement in the quality of sleep in a normal community sample. Our results corroborated the findings from a recent safety and tolerability study of extract Sceletium tortuosum (Zembrin) on sleep quality [21]. ...
Article
Full-text available
Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 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. Conclusion. 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. This trial is registered with ClinicalTrials.gov NCT01805518.
... group study (n = 37) (Nell et al., 2013). The safety and tolerability variables studied were vital signs, physical examination, 12-lead electrocardiogram, laboratory assessments (hematology, biochemistry, and urinalysis), and the recording of adverse events (AEs). ...
... The present studies are the first formal in vivo toxicological studies of an extract of S. tortuosum (Zembrin ® ) and provide supporting evidence for the safety and tolerability findings in the first clinical study (Nell et al., 2013). The repeated administration of Zembrin ® for 90 days by gavage to Wistar rats resulted in a NOAEL of 600 mg/kg bw/day. ...
... A small series of clinical case studies of subjects who ingested daily amounts of 50-100 mg of uncharacterized milled S. tortuosum raw material reported positive findings on mood and feelings of anxiety (Gericke, 2001), and an in vivo study of an uncharacterized extract of S. tortuosum in rats demonstrated a positive outcome on the behavioral effects of restraint stress (Smith, 2011). Positive effects on well-being, including improved stress coping and improved sleep, were noted in patient diaries by some participants taking extract S. tortuosum (Zembrin ® ) in the first clinical study of this extract (Nell et al., 2013). A recent double-blind placebo-controlled cross-over pharmaco-fMRI study of a single 25 mg dose administration of Zembrin ® in healthy university students demonstrated significant attenuation of amygdala reactivity to fearful faces under low Table 12 Organ weight relative to body weight (%) in the 90-day repeated oral toxicity study. ...
Article
A well-characterized standardized hydroethanolic extract of a traditionally recognized mak (mild) variety of Sceletium tortuosum, a South African plant with a long history of traditional ingestion, is marketed under the trade name Zembrin® as an ingredient for use in functional foods and dietary supplements. It is standardized to contain 0.35–0.45% total alkaloids (mesembrenone and mesembrenol ≥60%, and mesembrine <20%). A 14-day repeated oral toxicity study was conducted at 0, 250, 750, 2500, and 5000 mg/kg bw/d. A 90-day subchronic repeated oral toxicity study was conducted at 0, 100, 300, 450, and 600 mg/kg bw/d. Because S. tortuosum has a long history of human use for relieving stress and calming, a functional observation battery, including spontaneous locomotor activity measured using LabMaster ActiMot light-beam frames system, was employed. Several parameters, such as locomotion, rearing behavior, spatial parameters, and turning behavior were investigated in the final week of the study. No mortality or treatment-related adverse effects were observed in male or female Crl:(WI)BR Wistar rats in the 14- or 90-day studies. In the 14- and 90-day studies, the NOAELs were concluded as 5000 and 600 mg/kg bw/d, respectively, the highest dose groups tested.
... In a randomized, double-blind placebo-controlled parallel-group study involving healthy adult volunteers, Nell et al. (2013) investigated the safety and toxicity of two doses of Zembrin® (8 mg and 28 mg equivalent to 16 mg and 50 mg of dry plant material, respectively), taken once daily for three months. The variables studied were assessed using physical examination, vital signs, 12-lead electrocardiogram, different laboratory assessments (urinalysis, biochemistry, and hematology), and recording of adverse events. ...
... Indeed, the Koi-San of Africa have long since used S. tortuosum plant extracts to promote a sense of calm and relieve stress, reduce anxiety, improve mood, and enhance concentration . Clinical studies have concurred, showing S. tortuosum (25mg per day) to relieve anxiety and stress (Nell et al., 2013;Terburg et al., 2013). A single dose of Zembrin® was found to reduce psychological stress . ...
... In a randomized, double-blind placebo-controlled parallel-group study involving healthy adult volunteers, Nell et al. (2013) investigated the safety and toxicity of two doses of Zembrin® (8 mg and 28 mg equivalent to 16 mg and 50 mg of dry plant material, respectively), taken once daily for three months. The variables studied were assessed using physical examination, vital signs, 12-lead electrocardiogram, different laboratory assessments (urinalysis, biochemistry, and hematology), and recording of adverse events. ...
... Indeed, the Koi-San of Africa have long since used S. tortuosum plant extracts to promote a sense of calm and relieve stress, reduce anxiety, improve mood, and enhance concentration . Clinical studies have concurred, showing S. tortuosum (25mg per day) to relieve anxiety and stress (Nell et al., 2013;Terburg et al., 2013). A single dose of Zembrin® was found to reduce psychological stress . ...
Article
Ethnopharmacological relevance Sceletium tortuosum (L.) N.E.Br., the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. Aim of the review The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological, pre-clinical and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. Methods All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. Results Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, neuromodulatory, immunomodulatory, anti-HIV, neuroprotection) in in vitro or in vivo studies. While the plant has been studied in clinical populations, this has only been in healthy subjects, so that further study in pathological states remains to be done. Nevertheless, the aforementioned studies have demonstrated that S. tortuosum has potential for enhancing cognitive function and managing anxiety and depression. Conclusion As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.
... In a randomized, double-blind placebo-controlled parallel-group study involving healthy adult volunteers, Nell et al. (2013) investigated the safety and toxicity of two doses of Zembrin® (8 mg and 28 mg equivalent to 16 mg and 50 mg of dry plant material, respectively), taken once daily for three months. The variables studied were assessed using physical examination, vital signs, 12-lead electrocardiogram, different laboratory assessments (urinalysis, biochemistry, and hematology), and recording of adverse events. ...
... Indeed, the Koi-San of Africa have long since used S. tortuosum plant extracts to promote a sense of calm and relieve stress, reduce anxiety, improve mood, and enhance concentration . Clinical studies have concurred, showing S. tortuosum (25mg per day) to relieve anxiety and stress (Nell et al., 2013;Terburg et al., 2013). A single dose of Zembrin® was found to reduce psychological stress . ...
Article
Ethnopharmacological relevance Sceletium tortuosum (L.) N.E.Br, the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, and as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. Aim of the review The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. Methods All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. Results Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, immunomodulatory, anti-HIV, neuroprotection, enhancement of cognitive function) in in vitro or in vivo studies. This plant has not yet been studied in a clinical population, but has potential for enhancing cognitive function, and managing anxiety and depression. Conclusion As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.
... The most commonly reported AE was headache, with some abdominal pain and upper respiratory tract infections, all with greater incidence in the placebo group than in the treatment groups. Efficacy was not assessed, but unsolicited positive effects on well-being were noted by some participants taking extract, including improved coping with stress and sleep [49]. ...
Article
Modern-day regulatory systems governing conditions for how health products enter national markets constitute a barrier of access for traditional herbal medicines on an international level. Regulatory intentions are focused on ensuring consumers are being provided with safe, efficacious and high-quality products that, however, collaterally limit opportunities for traditional herbal medicinal products, especially those that do not already have a long-standing tradition of use established in the respective national marketplaces. This case study investigates and compares how a Southern African herbal medicine with great potential as an anxiolytic and mild antidepressant – Mesembryanthemum tortuosum L. [syn. Sceletium tortuosum (L.) N.E.Br.] aerial parts – fares internationally in today’s regulatory environments. It is argued that inadvertent regulatory favoritism combined with the lack of means for adequate protection of intellectual property may obstruct innovation by creating an almost insurmountable economical hurdle for successful product development and introduction of botanicals from developing countries into most of the world’s health product markets.
... This raises questions about bio-prospecting and the ethics of phyto-extraction, as well as questions about access and benefit sharing. Many studies have been driven by the commercial potential, including in vitro pharmacology experimentation, pre-clinical studies, clinical case studies and pilot randomized controlled clinical trials (Gericke & Viljoen 2008;Nell et al. 2013;Chiu et al. 2014;Dimpfel et al. 2016;Krstenansky 2017). These studies are concentrated on Sceletium and extracts of the plant material per se, in particular the alkaloids. ...
Presentation
Three ingredients exist inside any honeybee hive, wild or domesticated – yeast, beebread (transformed floral pollen) and honey (fructose and glucose). If combined with water these ingredients produce alcohol. Success depends on an accumulation of pharmacological knowledge, keen observation and an astute, flexible cognitive ability. Archaeological evidence from Border Cave, South Africa suggests that honey bee products were being used and consumed by early people 40, 000 years ago. In this presentation, Neil Rusch draws on the archaeological record in support of a long-term chronology involving bees, bow-hunting and arrow poison production. This better explains the early appearance of intentional fermentation. A deep time perspective also accounts for the occurrence of bees in the ethnography, rock paintings and mythology of the region. This presentation and others in the NC State University Seminar Series are published in: Jewell, M., Dunn, R.R., Vandegrift, M., Nichols, L.M., Ciccone, K., Dufresne, K., Gannon, K., Hill, C., Kittinger, A., Kittleson, S., & O'Reilly, R. (Eds.). (2021). Fermentology. Raleigh, NC: NC State University Libraries. https://doi.org/10.52750/679579
... The most commonly reported AE was headache, with some abdominal pain and upper respiratory tract infections, all with greater incidence in the placebo group than in the treatment groups. Efficacy was not assessed, but unsolicited positive effects on well-being were noted by some participants taking extract, including improved coping with stress and sleep [49]. ...
Article
Full-text available
Modern-day regulatory systems governing conditions for how health products enter national markets constitute a barrier of access for traditional herbal medicines on an international level. Regulatory intentions are focused on ensuring consumers are being provided with safe, efficacious and high-quality products that, however, collaterally limit opportunities for traditional herbal medicinal products, especially those that do not already have a long-standing tradition of use established in the respective national marketplaces. This case study investigates and compares how a Southern African herbal medicine with great potential as an anxiolytic and mild antidepressant – Mesembryanthemum tortuosum L. [syn. Sceletium tortuosum (L.) N.E.Br.] aerial parts – fares internationally in today’s regulatory environments. It is argued that inadvertent regulatory favoritism combined with the lack of means for adequate protection of intellectual property may obstruct innovation by creating an almost insurmountable economical hurdle for successful product development and introduction of botanicals from developing countries into most of the world’s health product markets.
... [90] S. tortuosum extract at the doses of 8 and 25 mg/day was well tolerated in healthy people for 3 months. [91] Kanna, however, is detected in forensics to be a component of 'designer drugs' or as adulterated (fake) marijuana, which confirms the psychotropic potential of S. tortuosum. [92,93] S. tortuosum is a component of dietary supplements of the pre-workout and brain/cognitive booster categories. ...
... [90] S. tortuosum extract at the doses of 8 and 25 mg/day was well tolerated in healthy people for 3 months. [91] Kanna, however, is detected in forensics to be a component of 'designer drugs' or as adulterated (fake) marijuana, which confirms the psychotropic potential of S. tortuosum. [92,93] S. tortuosum is a component of dietary supplements of the pre-workout and brain/cognitive booster categories. ...
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This review focuses on four new product categories of food supplements: pre‐workout, fat burner/thermogenic, brain/cognitive booster, and hormone/testosterone booster. Many food supplements have been shown to be contaminated with unauthorized substances. In some cases, the ingredients in the new categories of dietary supplements were medicinal products or new synthetic compounds added without performing clinical trials. Some of the new ingredients in dietary supplements are plant materials that are registered in the pharmacopoeia as herbal medicines. In other cases, dietary supplements may contain plant materials that have no history of human use and are often used as materials to “camouflage” stimulants. In the European Union, new ingredients of dietary supplements, according to European Food Safety Authority or unauthorized novel food. Furthermore, selected ingredients in dietary supplements may be prohibited in sports and are recognized as doping agents by World Anti‐Doping Agency.
... More recently, a standardized extract of Sceletium tortuosum (trademarked as Zembrin ®2 ) has accumulated a small body of evidence to support its safety, cognitive enhancing, anxiolytic properties, and identified potential biological mechanisms of action. With regards to safety, 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. With regards to cognitive functioning, Dimpfel, Schombert, and Gericke (2016) demonstrated a dose-dependent attenuation of spectral power following three acute doses of Zembrin ® (2.5, 5.0, and 10.0 mg/kg) to adult Fischer rats, and Chiu et al. (2014) demonstrated, in older human adults, improved cognitive set flexibility and executive function following 3 weeks of daily consumption (25 mg Zembrin ® per day). ...
Article
Full-text available
Objective To investigate the anxiolytic properties of a standardized extract of Sceletium tortuosum (trademarked―Zembrin®). Methods Two studies utilized a placebo‐controlled, double‐blind, between‐subject experimental design to investigate 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 min of the multitasking framework in study 1 and a 5‐min simulated public speaking task in study 2. Study 1 measured subjective experiences of mood at baseline, prestress induction, and poststress induction. Study 2 measured subjective experiences of anxiety and physiological indicators of stress (heart rate [HR] and galvanic skin response) at baseline, prestress induction, during stress induction, and poststress induction. Results A series of analysis of covariances (baseline entered as the covariate) revealed 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 HR. Taken together, results indicate that a single dose of Zembrin® can ameliorate laboratory stress/anxiety responding in healthy volunteers. Conclusion We provide the first tentative behavioral evidence to support the anxiolytic properties of Sceletium tortuosum (25 mg Zembrin®).
... This raises questions about bio-prospecting and the ethics of phyto-extraction, as well as questions about access and benefit sharing. Many studies have been driven by the commercial potential, including in vitro pharmacology experimentation, pre-clinical studies, clinical case studies and pilot randomized controlled clinical trials (Gericke & Viljoen 2008;Nell et al. 2013;Chiu et al. 2014;Dimpfel et al. 2016;Krstenansky 2017). These studies are concentrated on Sceletium and extracts of the plant material per se, in particular the alkaloids. ...
Article
Full-text available
In this paper I present the results of a fermentation experiment in which alcohol is produced by combining honey, water and moerwortel (Glia prolifera). The procedure and combination of ingredients follows an indigenous method, as was conveyed to the botanist Carl Thunberg by KhoeSan informants in the 18th century. Results of this experiment are contextualized using ethnohistorical and early traveller testimonies that suggest widespread use of honey-alcohol combined with plant material for psychotropic and medicinal purposes. This included kanna (Sceletium tortuosum), which produced a 'spiked' honey drink known as khadi. Controlled fermentation may have emerged as early as the MSA, together with manifestations of complex behaviour and mental processing that was cognisant and capable of using a suite of complementary botanical, technical and chemical methods for various applications, such as making arrow poison and the synthesis of compound materials for the manufacture of mastics, adhesives and pigment. An explanatory framework encompassing an MSA and deep-time perspective helps to explain the related themes of honey bees in southern San mythology, pictorial expression and fermentation practices. Published Online:13 Dec 2020. https://hdl.handle.net/10520/EJC-1e2a35c417
... This raises questions about bio-prospecting and the ethics of phyto-extraction, as well as questions about access and benefit sharing. Many studies have been driven by the commercial potential, including in vitro pharmacology experimentation, pre-clinical studies, clinical case studies and pilot randomized controlled clinical trials (Gericke & Viljoen 2008;Nell et al. 2013;Chiu et al. 2014;Dimpfel et al. 2016;Krstenansky 2017). These studies are concentrated on Sceletium and extracts of the plant material per se, in particular the alkaloids. ...
Conference Paper
ABSTRACT In this presentation I give the results of a fermentation experiment (anaerobic and aerobic respiration) in which alcohol is produced by combining honey, water and ‘moerwortel’ (Glia prolifera). The procedure and combination of ingredients follows an indigenous method, as was conveyed to the botanist Carl Thunberg by KhoeSan informants in the 18th century. In a second stage of the experiment ‘kanna’ (Sceletium tortuosum) was added to the recipe to produce ‘khadi’, a ‘spiked’ honey drink reported by the Abbé de la Caille in 1763. Results of this experiment are contextualised using ethno-historical and early traveller testimonies that suggest widespread use of alcohol-honey combined with plant material for psychotropic and medicinal purposes. Controlled fermentation may have emerged as early as the MSA together with manifestations of complex behaviour and mental processing that was cognisant and capable of using a suite of complimentary bio-tech and chemical methods for various applications, such as: making arrow poison and the synthesis of compound materials for the manufacture of mastics, adhesives and pigment. An explanatory framework encompassing an MSA and deep-time perspective helps to explain the related themes of honey bees in southern San mythology, pictorial expression and fermentation practices.
... A range of natural functional food ingredients may fulfill this promise [5,6], including probiotics (beneficial bacteria), prebiotics (fermentable fibers), and phytobiotics (phytonutrients with gut-health-promoting benefits). In particular, most [4-6, 10, 11], but not all [12] human trials have recently shown positive psychological outcomes for a number of nutrients including specific Lactobacillus (helveticus R0052; rhamnosus R0011) and Bifidobacterium (longum R0175) strains [5,[14][15]; unique oligosaccharide structures including galactooligosaccharide (GOS), isomaltooligosaccharide (IMO), and galactomannan [21][22][23][24][25][26][27][28][29][30][31][32][33]; and traditional herbal extracts such as polyphenol/flavonoids [34]; ashwagandha [35]; magnolia bark [36]; rafuma [37]; sceletium [38]; amino acids [39][40][41]; and various phytonutrients [42][43][44][45][46][47][48][49][50]. ...
Article
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Background: Interest in and knowledge of the gut microbiome has increased exponentially in the past decade. This once overlooked component of the gastrointestinal tract is now implicated in multiple aspects of human health, including mental (e.g. depression, anxiety, stress), metabolic (e.g. diabetes/obesity), neurological (e.g. Alzheimer’s, Parkinson’s, Autism Spectrum Disorder), gastrointestinal (e.g. irritable bowel syndrome, Crohn’s), and immunological (e.g. inflammation, cancer) wellness, among others. Previous research has demonstrated the “strain specificity” of probiotic therapy (e.g. Lactobacillus helveticus R0052 for serotonin/depression; Bifidobacterium longum R0175 for GABA/anxiety; Lactobacillus rhamnosus R0011 for cortisol/stress). Similarly, probiotic bacteria demonstrate different growth trajectories based on availability of preferred fiber substrates (e.g. prebiotics) and phytonutrients such as flavonoids/polyphenols (e.g. phytobiotics). Thus, our objective was two-fold: to determine the change in microbiome ecology/balance and to evaluate the psychological mood state following a coordinated pro-/pre-/phyto-biotic supplementation regimen. Methods: Thirty-two healthy subjects screened for “moderate” levels of psychological stress were randomly assigned to 1-month of Supplement (Amare Fundamentals, N=21) or matching Placebo (N=11). Microbiome balance was assessed in fecal samples using a PCR-based analysis (BiomeTracker) that has previously compared favorably to 16S sequencing for abundance quantification for major phyla/families of bacteria. Psychological mood state parameters were assessed using the validated Profile of Mood States survey (POMS) to generate scores for Global Mood State, and six sub-scales (Depression, Tension, Fatigue, Anger, Confusion, and Vigor). Results: Following supplementation, there was a significant increase in populations of “good” bacteria in the Supplement group (+28% Lactobacillus; +30% Bifidobacterium) and overall composite score (+17%) versus Placebo (p<0.05). Psychological indices were significantly improved in the Supplement group for both positive (+25% Global Mood; +44% Vigor) and negative (-64% Fatigue; -55% Depression; -54% Anger; -45% Tension; -43% Confusion) mood state parameters versus Placebo (p<0.05). Conclusion: The World Health Organization has identified mental wellness issues as the leading contributor to global health burden – highlighting the urgency to develop lifestyle interventions to effectively manage depression, anxiety, and stress. These results demonstrate the close relationship between microbiome balance and psychological parameters – and the utility of targeted supplementation to positively influence the gut-brain-axis for improved mental wellness.
... The most commonly reported AE was headache, with some abdominal pain and upper respiratory tract infections, all with greater incidence in the placebo group than in the treatment groups. Efficacy was not assessed, but unsolicited positive effects on well-being were noted by some participants taking extract, including improved coping with stress and sleep [49]. ...
... Especially interesting is the fact that this traditional masticatory and hypnotic shows no evidence of physical or psychological dependency and therefore has potential for application as replacement therapy, to break addictions to alcohol and drugs (Van Wyk and Gericke, 2000;Gericke and Viljoen, 2008;Van Wyk, 2011a). Recent clinical studies have shown not only that the product is safe but also that is enhances a range of neuroactivities related to anxiety, depression and cognitive functions (Nell et al., 2013). Although kougoed or canna is traditionally used as a masticatory, Pappe (1850Pappe ( -1868 reported that it is used by the colonists in the form of decoction or tincture to treat nervous conditions. ...
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A review is presented of Cape plants that have been (or still are) used as hot beverages (i.e., tisanes or “teas”, consumed primarily as food items but partly also as traditional medicines). Data are presented on the historical and contemporary ethnobotanical uses of 52 species from 15 Cape genera (Agathosma, Aspalathus, Catha, Cyclopia, Geranium, Helichrysum, Lessertia, Leysera, Mentha, Mesembryanthemum, Plecostachys, Rafnia, Stachys, Thesium and Viscum). The tradition of drinking tea (and coffee), introduced by early European settlers in the 17th century, appears to have stimulated the use of numerous indigenous plants as tea and coffee substitutes. The fact that Khoi and San vernacular names for tea plants have never been documented might indicate that the drinking of herbal tea or bush tea was not part of the indigenous Khoi and San culinary traditions in the pre-colonial era (before the introduction of tea and coffee to the Cape). Several Cape “teas” have remained poorly known or apparently lost their popularity (e.g. Leysera gnaphalodes, once considered to be the most widely used Cape tea) while others appear to be relatively recent inventions (e.g. rooibos tea, Aspalathus linearis, conspicuous by its absence in the early literature and first mentioned in the historical record in the late 19th century). In contrast, honeybush tea or Cape tea (Cyclopia species, first recorded in 1830) has remained popular since the 18th century but only recently became an important item of commerce. There is evidence that some species were mainly used as adulterants or to improve the flavour of the tea (e.g. by enhancing the fermentation process). Some Cape herbal teas with commercial potential as new functional foods currently lack scientific data on the main chemical constituents and their modes of action.
... Br. has been documented for its use in managing T2DM (Semenya and Potgieter, 2014), and for HIV and TB in the Eastern Cape, South Africa (Lawal et al., 2014) This species has also traditionally been used to treat chest complaints, colds, fevers and coughing (Philander, 2011). The plant has been found to be safe in a clinical trial (Nell et al., 2013). ...
... Extract Sceletium tortuosum (Zembrin ® ) has been shown to be safe and well tolerated in pre-clinical [6] and clinical studies [7]. The acute effects of extract Sceletium tortuosum (Zembrin ® ) administration in 16 healthy young adults was studied in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neuro-circuitry. ...
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The endemic South African succulent plant Sceletium tortuosum (L.) N.E. Br., family Mesembryathemaceae, is known as kanna in Nama, kougoed in Afrikaans, and sceletium in English. The plant has been used as a tea and as a masticatory for millennia by indigenous San hunter-gatherers and Nama pastoralists for endurance and well-being. It has been reported that the plant “gives strength to their limbs, and takes away pain, and makes their memory strong”. The current investigation aimed at the psychophysiological characterization of 25.0 and 50.0 mg of a special extract marketed as Zembrin® in comparison to placebo using a new methodology called “EnkephaloVision”. This combination of EEG Neurocode-Tracking and Eye-Tracking allows for concomitant analysis of time epochs of only 364 ms duration. Spectral EEG analysis during cognitive and emotional challenges revealed statistically significant increases of delta (p ® within the frontal brain. It is these same increases of slow waves in the frontal brain that are described in the literature during performance of mental tests. This indicates a positive effect of Zembrin® on the electrical activity of the brain during cognitive processing. In addition, alpha1 and alpha2 spectral power in the frontal brain was increased during several challenges including brain teasing, arithmetic calculations and performance of a memory test. From the literature, increases of spectral alpha1 power indicate a greater degree of calmness and may represent decreased depressive symptoms, while increases in alpha2 waves have been related to memory. Beta2 waves increased during mental performance in the presence of the higher dosage of Zembrin® in parietal, occipital and temporal brain regions. In comparison to placebo, Zembrin® induced frequency changes in the brain, which have been related to enhanced attention and memory. These results may represent a positive action of Zembrin® on cognitive and emotional processes in the brain.
... A proprietary standardized and characterized extract of cultivated Sceletium tortuosum (Zembrin s ), a dual 5-HT uptake inhibitor and PDE4 inhibitor (Harvey et al., 2011), was shown to be safe and well tolerated in pre-clinical and clinical studies (Murbach et al., 2014;Nell et al., 2013). The acute effects of Extract Sceletium tortuosum (Zembrin s ) administration in 16 healthy young adults was studied in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neuro-circuitry. ...
Article
Ethnopharmacological relevance: The endemic succulent South African plant, Sceletium tortuosum (L.) N.E. Br. (synonym Mesembryanthemum tortuosum L.), of the family Mesembryathemaceae, has an ancient oral tradition history of use by San and Khoikhoi people as an integral part of the indigenous culture and materia medica. A special standardized extract of Sceletium tortuosum (Zembrin(®)) has been developed and tested pre-clinically in rats, and clinically in healthy subjects. Aim of the study: The present investigation aimed at the construction of electropharmacograms of Zembrin(®) in the presence of three dosages (2.5, 5.0 and 10.0mg/kg), and comparative electropharmacograms and discriminatory analyses for other herbal extracts, citicoline and rolipram. Material and methods: Seventeen adult Fischer rats were each implanted with a set consisting of four bipolar concentric steel electrodes fixed by dental cement and three screws driven into the scalp. After two weeks of recovery from surgery the animals were adapted to oral administration by gavage and to experimental conditions (45min pre-drug period and 5 hours of recording after a rest of 5 minutes for calming down). Data were transmitted wirelessly and processed using a Fast Fourier Transformation (FFT). Spectral power was evaluated for 8 frequency ranges, namely delta, theta, alpha1, alpha2, beta1a, beta1b, beta2 and gamma power. Results: Zembrin(®) dose dependently attenuated all frequency ranges, to varying degrees. The most prominent was the statistically significant reduction in alpha2 and beta1a waves, correlated with activation of the dopaminergic and glutamatergic transmitter systems respectively. This feature is common to all synthetic and herbal stimulants tested to date. The second strongest effects were reduction in both the delta and the theta frequency ranges, correlated with changes in the cholinergic and norepinephrine systems respectively, a pattern seen in preparations prescribed for neurodegenerative diseases. Theta wave reduction in common with the delta, alpha2 and beta1 attenuation has been noted for analgesic drugs. Attenuation of alpha1 waves emerged during the highest dosage in all brain areas, a feature seen in all antidepressants. Discussion: The electropharmacogram of Zembrin(®) was compared to the electropharmacograms of herbal extracts archived in our database. Extracts of Oenothera biennis and Cimicifuga racemosa gave a very similar electropharmacograms to that of Zembrin(®), and extracts of Ginkgo biloba and Rhodiola rosea gave rather similar electropharmacograms to Zembrin(®). Linear discriminant analysis confirmed these similarities and demonstrated that all three dosages of Zembrin(®) plotted in close neighbourhood to each other. Citocoline, a synthetic compound originally developed for cognitive enhancement, had a similar electropharmacogram to Zembrin(®). Similarity to the electropharmacograms of the synthetic phosphodiesterase-4 inhibitor, rolipram, suggests Zembrin(®) has antidepressant and cognitive function enhancing potentential. Conclusion: The combined results from the electropharmacograms and comparative discriminatory analyses suggest that Zembrin(®) has dose dependent activity, with potential applications as a cognitive function enhancer, as an antidepressant, and as an analgesic.
... Given the large variation between different proprietary plant preparations from almost identical source material across many indigenous species (Smith and Krygsman, 2014b), it is important that as much as possible analytical data is provided with plant material, to enable integration of results in the literature. In contrast to recent reports on low-mesembrine containing extracts (Murbach et al., 2014;Nell et al., 2013) which have thus far failed to show any concrete evidence of anti-stress effects in in vivo modelswe report several desirable effects in this context in a Sceletium compound with high mesembrine content. ...
... To these could be added three cosmopolitan species, namely Centella asiatica, Trigonella foenum-graecum and Withania somnifera. A fifth species that may soon qualify as a truly African phytomedicine is Sceletium tortuosum (kanna or kougoed), with a range of potential uses in neurology and psychiatry (it is a hypnotic and sedative) (Nell et al., 2013;Chiu et al., 2014). In the case of functional foods and nutraceuticals, at least 10 out of a total of 56 species are African in origin (nearly 18%). ...
Article
Ethnopharmacological relevance: Data on the relative importance and research status of commercially relevant African medicinal plants are needed for developing new research strategies in order to stimulate much-needed ethnopharmacological research and to promote the commercialization of African plants. Aim of the study: To present an illustrated bird's eye view and comparative analysis of the relative popularity and importance of commercialised African medicinal plants. A comparison is made between the general popularity and commercial importance of the species (as indicated by their footprint on the World Wide Web) and their scientific popularity and importance (as indicated by the number of research publications). The inventory and review is strongly focussed to cover all or most of the medicinal plant raw materials in the international trade that are exported from African countries, with less emphasis on those that are regularly traded on local and regional markets within Africa. Materials and methods: The review is based on literature data, Scopus and Google searches, commercial information and the author's own experience and observations. Results: More than 5400 plant species are used in traditional medicine in Africa, of which less than 10% have been commercially developed to some extent. Africa is home to more than 80 valuable commercial species that are regularly traded on international markets, including phytomedicines (e.g. Harpagophytum procumbens and Pelargonium sidoides), functional foods (e.g. Adansonia digitata and Hibiscus sabdariffa) and sources of pure chemical entities (e.g. caffeine from Coffea arabica and yohimbine from Pausinystalia johimbe). According to the Scopus results, about 60% of all recent publications on African medicinal plants appeared in the last decade, with an average of 280 papers (28 per year) for 85 prominent species of international trade. The most popular African species for research (number of publications in brackets) were: Ricinus communis (5187), Aloe vera (2832), Catharanthus roseus (2653), Sesamum indicum (2534), Strophanthus gratus (2514), Coffea arabica (2431), Citrullus lanatus (2215), Momordica charantia (2047), Withania somnifera (1767), Trigonella foenum-graecum (1687), Acacia senegal (1373), Centella asiatica (1355), Griffonia simplicifolia (1010), Hibiscus sabdariffa (987), Tamarindus indica (973) and Catha edulis (947). The top species in terms of recent research interest (% of publications in last decade) were: Hoodia gordonii (95%), Cyclopia genistoides (93%), Sceletium tortuosum (90%), Agathosma betulina (89%), Pelargonium sidoides (86%), Boswellia papyrifera (85%), Lessertia (Sutherlandia) frutescens (84%), Boswellia sacra (83%), Mondia whitei (81%), Hibiscus sabdariffa (80%), Hypoxis hemerocallidea (80%) and Tylosema esculentum (80%). Both lists reflect the recent interest in functional foods and dietary supplements. Conclusion: Despite a marked recent increase in the number of publications on indigenous medicinal plants and dietary supplements, Africa lags behind Europe and Asia in terms of the number of products that have been commercialised and the percentage of the flora that is utilised for international trade. There is a tremendous potential for developing new crops and new products but much work remains to be done to generate more focussed and relevant pre-clinical data and convincing proof of concept through clinical studies.
... In the West, it has been used in multiple settings, including depression and anxiety management and was recently shown to elevate mood in a human clinical trial (zembrin.com; Nell et al., 2013). There are also anecdotal reports online to suggest that drug users are using the plant as an adjuvant to both legal and illegal substances to enhance effects. ...
... The combination of SSRIs and PDE4 inhibitors might therefore not only have synergistic therapeutic potential but may allow for lower PDE4 doses that are better tolerated. Zembrin has been found to be safe and well-tolerated at doses of 8 and 25 mg taken orally once a day in a randomized, double-blind, parallel-group, placebo-controlled clinical trial, supporting the ethnobotanical record of safe use of S. tortuosum (Nell et al, 2013). Here, we report a functional magnetic resonance imaging (fMRI) study that is the first to test the activity of S. tortuosum (Zembrin) in the human brain and is thereby also the first study on the effects of a dual PDE4 and 5-HT reuptake inhibitor in humans. ...
Article
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The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people, and subsequently by European colonial farmers as a psychotropic in tincture form. Over the last 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. The pharmacological actions of a standardized extract of the plant (Zembrin(®)) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we 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 cross-over 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 demonstrate for the first time the attenuating effects of Sceletium tortuosum on the threat circuitry of the human brain, and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.Neuropsychopharmacology accepted article preview online, 1 August 2013. doi:10.1038/npp.2013.183.
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Plants from the Sceletium genus (Aizoaceae) have been traditionally used for millennia by the Khoe and Khoen people in southern Africa, as an appetite suppressant as well as a mood elevator. In more recent times, this mood-elevating activity has been commercialised in the South African natural products industry for the treatment of anxiety and depression, with several products available both locally and abroad. Research on this species has seen rapid growth with advancements in analytical and pharmacological tools, in an effort to understand the composition and biological activity. The Web of Science (WoS) database was searched for articles related to ‘Sceletium’ and ‘Mesembrine’. These data were additionally analysed by bibliometric software (VOSviewer) to generate term maps and author associations. The thematic areas with the most citations were South African Traditional Medicine for mental health (110) and anxiolytic agents (75). Pioneer studies in the genus focused on chemical structural isolation, purification, and characterisation and techniques such as thin layer chromatography, liquid chromatography (HPLC, UPLC, and more recently, LC-MS), gas chromatography mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) to study mesembrine alkaloids. Different laboratories have used a diverse range of extraction and preanalytical methods that became routinely favoured in the analysis of the main metabolites (mesembrine, mesembranol, mesembranone, and Sceletium A4) in their respective experimental settings. In contrast with previous reviews, this paper identified gaps in the research field, being a lack of toxicology assays, a deficit of clinical assessments, too few bioavailability studies, and little to no investigation into the minor alkaloid groups found in Sceletium. Future studies are likely to see innovations in analytical techniques like leaf spray mass spectrometry and direct analysis in real-time ionisation coupled with high-resolution time-of-flight mass spectrometry (DART-HR-TOF-MS) for rapid alkaloid identification and quality control purposes. While S. tortuosum has been the primary focus, studying other Sceletium species may aid in establishing chemotaxonomic relationships and addressing challenges with species misidentification. This research can benefit the nutraceutical industry and conservation efforts for the entire genus. At present, little to no pharmacological information is available in terms of the molecular physiological effects of mesembrine alkaloids in medical clinical settings. Research in these fields is expected to increase due to the growing interest in S. tortuosum as a herbal supplement and the potential development of mesembrine alkaloids into pharmaceutical drugs.
Preprint
Plants from the Sceletium genus (Aizoaceae) have been traditionally used by the Khoe-Sān people in southern Africa, mainly for thirst and hunger relief, pain reduction and spiritual purposes, particularly Sceletium tortuosum . The research on this species has seen rapid growth with advancements in analytical and pharmacological tools. The Web of Science (WoS) database was searched for articles related to ‘Sceletium’ and ‘Mesembrine’. These data were additionally analysed by bibliometric software (VOSviewer) to generate term maps and author associations. The thematic areas with the most citations were, South African Traditional Medicine for mental health (110) and anxiolytic agents (75). Pioneer studies in the genus focused on chemical structural isolation, purification and characterization and techniques such as thin layer chromatography, liquid chromatography (HPLC, UPLC and more recently, LC-MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) to study mesembrine alkaloids. Different laboratories have used a diverse range of extraction and pre-analytical methods that become routinely favoured in the analysis of the main metabolites (mesembrine, mesembranol, mesembranone and Sceletium A4) in their respective experimental settings. In contrast with previous reviews, this paper identified gaps in the research field, being a lack of toxicology assays, a deficit of clinical assessments, too few bioavailability studies and little to no investigation into the minor alkaloid groups found in Sceletium . Future studies are likely to see innovations in analytical techniques like leaf spray mass spectrometry and direct analysis in real-time ionization coupled with high-resolution time-of-flight mass spectrometry (DART-HR-TOF-MS) for rapid alkaloid identification and quality control purposes. While S. tortuosum has been the primary focus, studying other Sceletium species may aid in establishing chemotaxonomic relationships and addressing challenges with species misidentification. This research can benefit the nutraceutical industry and conservation efforts for the entire genus. At present, little to no pharmacological information is available in terms of the molecular physiological effects of mesembrine alkaloids in medical clinical settings. Research in these fields is expected to increase due to the growing interest in S. tortuosum as a herbal supplement and the potential development of mesembrine alkaloids into pharmaceutical drugs.
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The intranasal route of drug administration offers an opportunity to bypass the blood–brain barrier and deliver compounds directly into the brain. Scientific evidence exists for medicinal plants (e.g., Centella asiatica and Mesembryanthemum tortuosum) to treat central nervous system conditions such as anxiety and depression. The ex vivo permeation of selected phytochemicals (i.e., asiaticoside and mesembrine) has been measured across excised sheep nasal respiratory and olfactory tissue. Permeation studies were conducted on individual phytochemicals and C. asiatica and M. tortuosum crude extracts. Asiaticoside exhibited statistically significantly higher permeation across both tissues when applied alone as compared to the C. asiatica crude extract, while mesembrine permeation was similar when applied alone or as M. tortuosum crude extract. Permeation of all the phytocompounds was similar or slightly higher than that of the drug atenolol across the respiratory tissue. Permeation of all the phytocompounds was similar to or slightly lower than that of atenolol across the olfactory tissue. In general, the permeation was higher across the olfactory epithelial tissue than across the respiratory epithelial tissue and therefore showed potential for direct nose-to-brain delivery of the selected psychoactive phytochemicals.
Chapter
Mesembryanthemum tortuosum L. (Aizoaceae) was previously classified as Sceletium tortuosum and is still widely referred to under that name in literature. Locally, the plant is known as ‘kanna’. The small scrambling succulent is endemic to South Africa and is found in the arid areas of the Western, Eastern and Northern Cape provinces. For centuries, the Khoi and San people used the aerial parts in the form of a masticant or infusion, as a mood enhancer, to promote sleep and to soothe digestive conditions. After traditional fermentation to boost its psychoactive properties, the remedy is referred to as ‘kougoed’. The plant has been fully commercialised and selected chemotypes are cultivated as a source of raw material. Products are used for the management of mild depression, anxiety, insomnia, weak appetite, stress, bulimia, obsessive compulsive disorder and to alleviate drug-dependence. The psychoactive properties of the plant are attributed to the presence of mesembrine-type alkaloids. This monograph is a record of the ethnobotany, and the extensive research carried out to study the phytochemistry, in vitro and in vivo biological and pharmacological properties of M. tortuosum, as well as its toxicity profile. High-performance thin-layer chromatography (HPTLC) and ultra-performance liquid chromatography coupled to mass spectrometry (UPLC–MS) were used to establish typical chemical fingerprints of the plant. The marker compounds, mesembrenol, mesembranol, mesembrenone and mesembrine, were identified after both HPTLC and UPLC–MS analyses.
Thesis
The study focused on an investigation on the use, availability and traditional ecological knowledge of medicinal plants in Mangaung and Thabo Mofutsanyana district in the Free State province. A total of 48 traditional healers, muthi shops and street markets participated in this study. The investigation was carried out in 2018, and data were collected through the use of questionnaires and participants were located through snowball and convenience sampling. As compared to other provinces in South Africa, there is a lack of documented information on the harvesting, use, availability and storage of medicinal plants in the Free State Province of South Africa. Traditional knowledge has been declining from generation to generation, while the demand for medicinal plants are increasing. The absence of documented information records adds to the fragility of cultural knowledge in the Free State province. The results of the study revealed that 89 plant species from 72 genera represented by 43 families are used as medicinal plants in the study area to treat 56 ailments. The most commonly used families with more than two species were Asteraceae, Fabaceae, Hyacinthaceae, Apocynaceae, Geraniaceae, Amaryllidaceous and the remaining 37 families have two or one species used for medicinal purposes. The highest reported species were Pachycarpus rigidus, Dicoma anomala, Hypoxis hemerocallidea and Helichrysum caespititium. Roots and leaves were most harvested in the wild habitat and the growth type mostly harvested was perennial herbs followed by bulbs. The most reported method of preparation and route of administrating medicinal plant material was boiling of a powder in water to drink. The study found that there are many medicinal plants which are used to treat a wide spectrum of human ailments such as flu, headache, stomach pain, tooth ache and diarrhoea. The majority of plants reported were indigenous, listed under least concern status (LC) on the red data list and are easily available from the natural area. Knowledge sharing differ from traditional healers, muthi shops and street markets; some participants freely share the knowledge while others keep it secret.
Article
Ethnopharmacological relevance Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. Aim of the study To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. Materials and methods The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. Results Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. Conclusions Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.
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Sceletium tortuosum (L.) N.E.Br. (Mesembryanthemaceae), commonly known as kanna or kougoed, is an effective indigenous medicinal plant in South Africa, specifically to the native San and Khoikhoi tribes. Today, the plant has gained strong global attraction and reputation due to its capabilities to promote a sense of well-being by relieving stress with calming effects. 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. Various studies have revealed that extracts of the plant have numerous biological properties and isolated alkaloids of Sceletium tortuosum are currently being used as dietary supplements for medicinal purposes and food. Furthermore, current research has focused on the commercialization of the plant because of its treatment in clinical anxiety and depression, psychological and psychiatric disorders, improving mood, promoting relaxation and happiness. In addition, several studies have focused on the isolation and characterization of various beneficial bioactive compounds including alkaloids from the Sceletium tortuosum plant. Sceletium was reviewed more than a decade ago and new evidence has been published since 2008, substantiating an update on this South African botanical asset. Thus, this review provides an extensive overview of the biological and pharmaceutical properties of Sceletium tortuosum as well as the bioactive compounds with an emphasis on antimicrobial, anti-inflammatory, anti-oxidant, antidepressant, anxiolytic, and other significant biological effects. There is a need to critically evaluate the bioactivities and responsible bioactive compounds, which might assist in reinforcing and confirming the significant role of kanna in the promotion of healthy well-being in these stressful times.
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Objectives: Plant-based medicines have had a long-standing history of use in psychiatric disorders. Highly quantified and standardized extracts or isolates may be termed "phytoceuticals," in a similar way that medicinal nutrients are termed as "nutraceuticals." Over the past 2 decades, several meta-analyses have examined the data for a range of plant-based medicines in the treatment of psychiatric disorders. The aim of this international project is to provide a "meta-review" of this top-tier evidence. Methods: We identified, synthesized, and appraised all available up to date meta-analyses... of randomized controlled trials (RCTs) reporting on the efficacy and effectiveness of individual phytoceuticals across all major psychiatric disorders. Results: Our systematic search identified 9 relevant meta-analyses of RCTs, with primary analyses including outcome data from 5,927 individuals. Supportive meta-analytic evidence was found for St John's wort for major depressive disorder (MDD); curcumin and saffron for MDD or depression symptoms, and ginkgo for total and negative symptoms in schizophrenia. Kava was not effective in treating diagnosed anxiety disorders. We also provide details on 22 traditional Chinese herbal medicine formulas' meta-analyses (primarily for depression studies), all of which revealed highly significant and large effect sizes. Their methodology, reporting, and potential publication bias were, however, of marked concern. The same caveat was noted for the curcumin, ginkgo, and saffron meta-analyses, which may also have significant publication bias. Conclusions: More rigorous international studies are required to validate the efficacy of these phytoceuticals before treatment recommendations can be made. In conclusion, the breadth of data tentatively supports several phytoceuticals which may be effective for mental disorders alongside pharmaceutical, psychological therapies, and standard lifestyle recommendations.
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Zembrin® is a botanical functional food and dietary supplement ingredient sold in the USA, and Canada for enhancing mood, decreasing anxiety and stress and improving cognitive function under stress. It is a proprietary extract of a cultivated selection of Sceletium tortuosum. The present investigation aimed at the measurement of the effect of 25 or 50 mg of Zembrin® in comparison to placebo after daily repetitive intake for 6 weeks. Sixty healthy male (n = 32) and female (n = 28) right-handed 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 (CATEEM®) before and 1 h after intake. Six cognitive tests were performed: 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, Hamilton Anxiety Rating Scale and a sleep questionnaire. Quantitative EEG revealed increases of delta activity during performance of the d2-test, the number identification and number connection test in the fronto-temporal brain region. Higher theta activity was seen during relaxation and performance of the d2-test after intake of 50 mg 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 revealed a projection of Zembrin® data into the vicinity of the calming preparation Calmvalera tablets and a Ginkgo-Ginseng mixture. Statistically significant improvement during performance of the arithmetic calculation test and number connection test was documented. The HAM-A anxiety score revealed a statistically significant decrease (p = 0.03) after six weeks. Zembrin® showed significant activity on three levels of evidence: questionnaires, psychometry and quantitative EEG. The results indicate that in healthy people Zembrin® improves some aspects of cognitive function, decreases anxiety, and may enhance mood.
Article
Ethnopharmacological relevance: Mesembrine alkaloids are considered to be the primary active constituents of the South African medicinal plant Sceletium tortuosum (L.) N.E.Br. (Aizoaceae), and it is used as the dried or fermented aerial material from the plant, which is known as kanna (aka, channa, kougoed). Traditional regional use ranged from relieving thirst, mild analgesia, and alteration of mood. Current interest has focused primarily on the antidepressant action of preparations based on the plant and commercialization is expanding the recognition and availability of these preparations. Materials and methods: Searches for the keywords "Sceletium or mesembrine" were performed in "PubMed-NCBI", "Chemical Abstracts SciFinder" and "Thomson Reuters Web of Science" databases in addition to the inclusion of references cited within prior reviews and scientific reports. Additionally the "SciFinder" database was searched using 3a-phenyl-cis-octahydroindole in the SciFinder Substructure Module (SSM). Plant taxonomy was validated by the database "The Plant List". Results: This review focuses on the chemistry, analysis, and pharmacology of the mesembrine alkaloids. Despite a long history of medicinal used 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. They are serotonin reuptake inhibitors, which provides a rationale for the plant's traditional use as an antidepressant, but other actions are beginning to appear in the literature. Additionally, mesembrenone has reasonably potent PDE4 inhibitory activity. This review intends to provide an overview of the available literature, summarize the current findings, and put them in perspective with earlier studies and reviews.
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Ethnopharmacological relevance: Sceletium tortuosum (L.) N.E. Br. has been reported to elevate mood, reduce anxiety and stress and alleviate pain. Aim of study: This study sought to examine the effects of an S. tortuosum alkaloid enriched fraction in the chick anxiety-depression model, a model that shows high predictive validity as a pharmacological screening assay. Material and methods: Socially-raised male Silver Laced Wyandotte chicks (4-6 days old) were given IP vehicle, imipramine (10mg/kg), or S. tortuosum fraction (10, 20, 30mg/kg in Exp. 1 or 50, 75, 100mg/kg in Exp. 2) 15min prior to a 60m isolation test period in which distress vocalizations (DVoc) were continuously recorded. Results: Vehicle chicks displayed high DVoc rates in the anxiety phase (first 3m). DVoc rates declined about 50% (i.e., behavioral despair) in the depression phase (30-60m). S. tortuosum fraction at 75 and 100mg/kg decreased DVoc rates during the anxiety phase indicative of an anxiolytic effect. Imipramine, but not S. tortuosum groups, increased DVoc rates in the depression phase indicative of an antidepressant effect. Conclusions: The findings suggest that an alkaloid enriched S. tortuosum fraction may benefit some forms of stress-related disorders.
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Glia are starting to be accepted as the equal of neurons. Glia's role in stress and disease as well as the latest glial modulators are reviewed. Environmental enrichment and exercise can increase intelligence, a buffer against stress, most likely via glial involvement. Cerebral dominance is also related to how glia respond to stress resulting in psychiatric illness. Glial effects on depression and schizophrenia are reviewed. Astrocytes, microglia, NG2 cells, and oligodendrocytes all contribute. Suicidal ideation can increase the permeability of the BBB resulting in the increase in serum levels of a glial protein S100B that has become a marker for the intensity of suicidal risk. Microglia form one of the bases of the inflammatory theory of psychiatric disorders. Minocycline, adenosine and cAMP inhibitors, such as PDE-4 inhibitors, have been used to modulate the microglia, with positive results in psychiatric illness. Controlling the microglia can even be protective against drug abuse. Recently a "glymphatic" system has been discovered in mice that if applicable to humans means that we clean out our brains in sleep.
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Mesembrine and mesembrenone are the main alkaloids of Sceletium tortuosum, a plant species that was used for sedation and analgesia by the KhoiSan, previously known as Hottentots, a tribe in South Africa. After fermentation, the obtained preparation called "Kanna" or "Kougoed" was used by chewing, smoking, or sniffing. Today, Kanna gains popularity by drug users as legal high. For monitoring such consumption, metabolism studies are mandatory because the metabolites are mostly the analytical targets, especially in urine. Therefore, the metabolism of both alkaloids was investigated in rat urine and pooled human liver preparations after several sample work-up procedures. As both alkaloids were not commercially available, they were isolated from plant material by Soxhlet extraction, and their identity confirmed by NMR. The metabolites were identified using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography coupled to linear ion trap high resolution mass spectrometry (LC-HR-MS(n)). Both alkaloids were O- and N-demethylated, dihydrated, and/or hydroxylated at different positions. The phenolic metabolites were partly excreted as glucuronides and/or sulfates. Most of the phase I metabolites identified in rat urine could be detected also in the human liver preparations. After a common user's low dose application of mesembrine, mainly the O- and N demethyl-dihydro, hydroxy, and bis-demethyl-dihydro metabolites, and in case of mesembrenone only the N-demethyl and the N-demethyl-dihydro metabolite could be detected in rat urine using the authors' standard urine screening approaches (SUSA) by GC-MS or LC-MS(n). Thus, it should be possible to monitor a consumption of mesembrine and/or mesembrenone assuming similar pharmacokinetics in humans.
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This paper provides an overview of the expansive South African biodiversity, which contributes to the historical use of medicinal plants and the large existence of traditional healers. It also underscores the lack of acknowledgment that traditional medicines are given by local authorities and the flaws that exist within present validation systems. The author also briefly highlights a few indigenous South African medicinal plants to draw attention to some recent developments.
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The South African plant Sceletium tortuosum has been known for centuries for a variety of traditional uses, and, more recently, as a possible source of anti-anxiety or anti-depressant effects. A standardised extract Zembrin(®) was used to test for pharmacological activities that might be relevant to the ethnopharmacological uses, and three of the main alkaloids were also tested. A standardised ethanolic extract was prepared from dried plant material, along with the purified alkaloids mesembrine, mesembrenone and mesembrenol. These were tested on a panel of receptors, enzymes and other drug targets, and for cytotoxic effects on mammalian cells. The extract was a potent blocker in 5-HT transporter binding assays (IC(50) 4.3 μg/ml) and had powerful inhibitory effects on phosphodiesterase 4 (PDE4) (IC(50) 8.5 μg/ml), but not other phosphodiesterases. There were no cytotoxic effects. Mesembrine was the most active alkaloid against the 5-HT transporter (K(i) 1.4 nM), while mesembrenone was active against the 5-HT transporter and PDE4 (IC(50)'s<1 μM). 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. The activities relate to the presence of alkaloids, particularly mesembrine and mesembrenone.
Article
It is probable that plants of the genus Sceletium (Mesembryanthemaceae) have been used as masticatories and for the relief of thirst and hunger, to combat fatigue, as medicines, and for social and spiritual purposes by San hunter-gatherers (historically referred to as Bushmen) and Khoi pastoralists (historically referred to as Hottentots) for millennia before the earliest written reports of the uses of these plants by European explorers and settlers. The oral-tradition knowledge of the uses of Sceletium by indigenous peoples has largely been eroded over the last three centuries due to conflicts with settlers, genocidal raids against the San, loss of land, the ravages of introduced diseases, and acculturation. Wild resources of Sceletium have also been severely diminished by over-harvesting, poor veld-management, and possibly also by plant diseases. Sceletium was reviewed almost a decade ago and new results have emerged substantiating some of the traditional uses of one of South Africa's most coveted botanical assets, and suggesting dietary supplement, phytomedicine and new drug applications. This review aims to collate the fragmented information on past and present uses, the alkaloid chemistry and pharmacological evidence generated on Sceletium.
Article
The use by the Khoisan of South Africa of Sceletium plants in psychoactive preparations has often been alluded to in the literature. However, much of it is fragmentary and contradictory. The current review reassembles the historical data recorded over a 300-year period, describes techniques for the preparation and use of "kougoed' from plants of Sceletium and documents the subjective experiences of a number of contemporary users. Apart from chewing the dried product, after "fermentation', there are reports of uses as tinctures for sedation and analgesia, chewing the material directly and smoking the residue after chewing. The symbolic connections of Sceletium with eland antelopes, the "trance animals' par excellence of the San hunter-gatherers is noted. Observations by Paterson (1789) and reports of contemporary users indicate a synergism and potentiation with smoked Cannabis. There is no evidence to support the view that "kougoed' or Sceletium alkaloids are hallucinogenic. The alkaloid distribution in Sceletium and other members of the family Mesembryanthemaceae are considered. Chemical studies have indicated as many as nine alkaloids in Sceletium which fall into three distinct structural categories. Mesembrine, the alkaloid first isolated and named is not the dominant constituent of plants and is weakly narcotic. Evidence is assembled to suggest that traditional and contemporary methods of preparation serve to reduce levels of potentially harmful oxalates, which are found in Sceletium and other Mesembryanthemaceae. It is concluded that there is a need for further pharmacological studies on these alkaloids, based on their narcotic-anxiolytic properties, strong synergism with other psychomimetics, moderate toxicity and anti-cancer activity.
The Medicinal and Poiso-nous Plants of Southern and Eastern Africa
  • Watt Jm
  • Brandwijk Mg E & S Livingstone Breyer
  • Ltd
Watt JM, Breyer-Brandwijk MG. The Medicinal and Poiso-nous Plants of Southern and Eastern Africa. London: E & S Livingstone Ltd., 1960:1457.
Common Names of South African Plants. Botanical Survey Memoir No. 35
  • C A Smith
Smith CA. Common Names of South African Plants. Botanical Survey Memoir No. 35. Republic of South Africa: Botanical Research Institute, Department of Agricultural Technical Services, 1966:642.
Simon van der Stel's Journey to Namaqualand in 1685
  • G Waterhouse
  • Dewet Gc
  • Pheiffer
Waterhouse G, DeWet GC, Pheiffer RH, eds. Simon van der Stel's Journey to Namaqualand in 1685. Cape Town: Human & Rousseau, 1979.
The Present State of the Cape of Good Hope
  • P Kolben
Kolben P. The Present State of the Cape of Good Hope. Vol. 1, 2 nd ed. G. Medley (trans.) W. Innys and R. Matiby. London, 1738.
Pharmaceutical compositions containing mesembrine and related compounds
  • N Gericke
  • B-E Van Wyk
Gericke N and van Wyk B-E. Pharmaceutical compositions containing mesembrine and related compounds. US Patent 6,288,104, 1999.
Uit Die Veldapteek. Cape Town: Tafelberg
  • B Rood
Rood B. Uit Die Veldapteek. Cape Town: Tafelberg, 1994:115.