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Sceletium tortuosum (Zembrin®) ameliorates experimentally induced anxiety in healthy volunteers

Authors:

Abstract

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®).
Received: 27 January 2020
-
Revised: 13 June 2020
-
Accepted: 30 June 2020
DOI: 10.1002/hup.2753
SHORT COMMUNICATION
Sceletium tortuosum (Zembrin
®
) ameliorates experimentally
induced anxiety in healthy volunteers
Jonathon Reay
1
|Mark A. Wetherell
2
|Emma Morton
2
|James Lillis
1
|
Vladimir Badmaev
3
1
Department of Psychology, School of Social
Sciences, Humanities & Law, Teesside
University, Middlesbrough, UK
2
Department of Psychology, Stress Research
Group, Northumbria University, Newcastle
uponTyne, UK
3
American Medical Holdings Inc., New York,
New York, USA
Correspondence
Jonathon Reay, Department of Psychology,
School of Social Sciences, Humanities & Law,
Teesside University, Middlesbrough TS13BX,
UK.
Email: j.reay@tees.ac.uk
Abstract
Objective: To investigate the anxiolytic properties of a standardized extract of
Sceletium tortuosum (trademarkedZembrin
®
).
Methods: Two studies utilized a placebocontrolled, doubleblind, betweensubject
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 5min 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
®
).
KEYWORDS
anxiety, anxiolytic, Sceletium tortuosum, stress, zembrin
1
|
INTRODUCTION
Sceletium tortuosum (L.) N.E.Br. (Mesembryanthemaceae) is used by
some tribal people of South Africa to reduce feelings of pain and hun-
ger, ameliorate stress, and enhance mental and physical performance
(see review by Gericke & Viljoen, 2008). In western cultures, the pur-
ported therapeutic properties of Sceletium tortuosum have received
limited scientific scrutiny; however, early research is promising. For
example, Smith (2011) reported evidence of the anxiolytic properties
of a low dose (5 mg/kg/day) but not a higher dose (20 mg/kg/day) of
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© 2020 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.
Hum Psychopharmacol Clin Exp. 2020;e2753. wileyonlinelibrary.com/journal/hup
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https://doi.org/10.1002/hup.2753
Sceletium tortuosum on restraintinduced anxiety in rats.
1
Similarly,
Hirabayashi, Ichikawa, Yoshi, Uchino, and Shimada (2004) demon-
strated reduced stress and anxiety in cats administered 10 mg/kg/day.
More recently, a standardized extract of Sceletium tortuosum (trade-
marked 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 dosedependent 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).
With regard to the anxiolytic effect of Zembrin
®
, two studies have
identified potential biological mechanisms of action, the first demon-
strated Zembrin
®
to be a dual serotonin (5HT) transporter blocker and
selective inhibitor of phosphodiesterase4 (Harvey, Young, Viljoen, &
Gericke, 2011) and the second demonstrated a single 25 mg dose of
Zembrin
®
could reduce anxietyrelated amygdala reactivity and
attenuated amygdala–hypothalamus coupling in healthy young vol-
unteers 2 h postdose (Terburg et al., 2013). To the authors' knowledge,
the anxiolytic effects of Zembrin
®
are yet to be investigated in a
behavioral study; therefore, we report for the first time the results of
two behavioral studies that directly tested the anxiolytic properties of
Zembrin
®
. The first study also investigated two additional purported
propertiesthe effects on feelings of hunger and memory perfor-
mance. We predict that Zembrin
®
will ameliorate stress/anxiety
responding to acute laboratory stressors in healthy volunteers.
2
|
METHODS
2.1
|
Design
Both studies utilized a placebocontrolled, doubleblind, between
subject experimental design to investigate the anxiolytic effects of a
single dose of Zembrin
®
(25 mg) in healthy volunteers. Study 1
measured at baseline, prestress, and poststress induction. Study 2
measured at baseline, prestress, during stress, and poststress induction.
2.2
|
Participants
Study 1: Twenty (six male) healthy volunteers (mean age 19.6 years;
SD 1.09; body mass index 20.87). Study 2: Twenty (11 male) healthy
volunteers (mean age 21.3 years; SD 1.38).
2.3
|
Stress induction
2.3.1
|
Study 1: Multitasking framework
The multitasking framework (MTF; Purple Research Solutions) is a
computerized stressor that reliably elicits cognitive demand, negative
affect, stress, and anxiety (Scholey et al., 2009; Wetherell & Carter,
2014). The MTF requires participants to attend to four tasks simul-
taneously that vary in terms of time pressure and/or difficulty; tasks
are performancedriven and demand is manipulated through
instructing participants to achieve as high a score as they can. The
current version consisted of four tasks (visual warning, mail alert,
telephone entry, and maths), which required visual monitoring,
accurate data entry, and mental arithmetic (for a detailed description
of tasks, see Wetherell & Carter, 2014).
2.3.2
|
Study 2: Simulated public speaking task
On the day of testing, participants were informed that they would
be completing a 5min public speech to outline why they would be
the most suitable applicant for a job of their choosing. Following a
2min preparation period, participants stood in front of the
researcher and performed their speech, the researcher gave no
feedback, and participants were required to continue speaking for
the duration of the task. Participants were also informed that their
speech would be recorded and their performance considered by a
panel of experts.
2.4
|
Outcome variables
2.4.1
|
Study 1
Perceived Stress Scale (PSS; Cohen & Williamson, 1988): The PSS
was used to measure perceptions of stress during the previous
month. A higher score represents higher feelings of stress.
Bond–Lader Visual Analogue Scales (Bond & Lader, 1974): A
16item scale provides three mood dimensions as follows: (1) alert,
(2) calm, and (3) content. The Bond–Lader was utilized to confirm
stress induction and to assess any impact of treatment (scale uti-
lized in study 2 too).
Visual Analogue Hunger Scale: A 100mm line anchored by “not
hungry” to “very hungry.” Participants crossed the line at the point
that best described their current feeling. A score of 0 (not hungry) to
a score of 100 (very hungry). If results reveal a treatment effect on
hunger, hunger will be included as a covariate.
Immediate word recall: Two sets of 20 concrete nouns were
created giving an A–B or B–A order. Each list was presented for 60 s,
and participants were given 60 s for recall.
The National Aeronautics and Space Administration task load
index (NASATLX; Hart & Staveland, 1988): The NASATLX measures
six workload domains. Three of which reflect the respondents
perceived demands of the task (mental demand, physical demand,
1
However, numerous side effects were also reported for both doses.
2
The hydroethanolic extract of a select variety of Sceletium tortuosum plant standardized to
contain 0.35%–0.45% total alkaloids: mesembrenone and mesembrenol 60%, and
mesembrine <20%, HGH Inc.
2 of 7
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REAY
ET AL.
and temporal demand), and three reflect the interaction between the
task and the respondent (effort, perceived performance, and
frustration).
2.4.2
|
Study 2
State–Trait Anxiety Inventory (STAI; Spielberger, 2010): A 40item
inventory split into two 20item sections. The first focuses on state
anxiety whereas the second focuses upon trait anxiety.
Visual Analogue Anxiety (VAa) Mood Scale (Wetherell, Craw,
Smith, & Smith, 2017): A 10point scale anchored by “not at all” to
“very anxious.” Participants marked the point that best describes
their current feeling. A score of 0 (not at all feeling anxious) to a
score of 10 (feeling very anxious).
Biopac (Biopac Systems, Inc, Unit MP35): Heart rate (HR) and
galvanic skin response (GSR) were utilized as physiological indicators
of anxiety.
2.5
|
Procedure
All participants provided written informed consent and attended
between 8:30 a.m. and 10 a.m. Participants confirmed they had not
consumed food or drink (water being an exception) since 8 p.m. and
were randomly allocated placebo or Zembrin
®
treatment condition.
Ethical approval was granted from the Department of Psychology at
Northumbria University for study 1 and from the School of Social
Science, Business and Law at Teesside University for study 2. Par-
ticipants completed task order as detailed in Figure 1.
2.6
|
Statistical analysis
To confirm the absence of any group difference in “background”
levels of stress/anxiety, baseline scores from the PSS (study 1) and
STAI (study 2) were analyzed by oneway between group analysis of
variance (ANOVA).
2.6.1
|
Study 1
Placebo data for the Bond–Lader was analyzed by oneway repeated
measures ANOVA to confirm stress induction. To explore treatment
effects, each outcome measure was subject to an analysis of
covariance (ANCOVA; baseline score was entered as the covariate).
Oneway ANOVA was utilized for each domain of the NASATLX (see
Table 1 for means and SE).
FIGURE 1 Study protocol for study 1 and
study 2. Dosage ¼25 mg Sceletium tortuosum
(trademarked Zembrin
®
) or placebo. BL,
Bond–Lader Visual Analogue Mood Scale; IWR,
immediate word recall; PSS, Perceived Stress
Scale; STAI(s), State–Trait Anxiety Inventory
(state score); STAI (t), State–Trait Anxiety
Inventory (trait score); TLX, the National
Aeronautics and Space Administration task load
index; VAa, Visual Analogue Anxiety Scale; VAh,
Visual Analogue Hunger Scale
REAY ET AL.
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2.6.2
|
Study 2
Placebo data for the STAI(s), VAa scale, HR, and GSR were analyzed
by oneway repeated measures ANOVA to confirm stress induction.
To explore treatment effects, each outcome was subject to ANCOVA
(baseline score was entered as the covariate) (See Table 2 for means
and SE).
3
|
RESULTS
3.1
|
Study 1
3.1.1
|
Background stress
PSS: No significant difference between placebo and Zembrin
®
group
(F(1,18) ¼0.76, p ¼0.785).
3.1.2
|
Stress induction
A main effect of time on feelings of alertness (F(1,18) ¼5.74, p ¼0.012)
and calmness (F(1,18) ¼9.87, p ¼0.001) confirm stress induction.
3.1.3
|
Effect of treatment
No treatment effects observed on any outcome measure.
3.2
|
Study 2
3.2.1
|
Background anxiety
STAI (trait): No difference between placebo and Zembrin
®
group
(F(1,18) ¼0.105, p ¼0.750).
TABLE 1Study 1: Means and SE for
each outcome measure at baseline and
each measurement point postdose
Baseline Prestress Poststress
Mean SE Mean SE Mean SE
Perceived stress Zembrin
®
22.2 2.8
Placebo 23.3 2.8
Mental demand Zembrin
®
64.1 4.65
Placebo 63.7 4.65
Physical demand Zembrin
®
26.8 6.64
Placebo 22.3 6.64
Temporal demand Zembrin
®
62.7 5.65
Placebo 49.6 5.65
Effort Zembrin
®
61.5 4.40
Placebo 64.8 4.40
Performance Zembrin
®
64.4 5.08
Placebo 63.3 5.08
Frustration Zembrin
®
38.2 6.83
Placebo 31.3 6.83
Hunger scale Zembrin
®
43.5 7.44 58.95 2.48
Placebo 69.5 2.72 59.04 2.30
Word recall (number correct) Zembrin
®
8.4 0.41 8.56 0.86
Placebo 9.9 0.53 9.91 0.81
Word recall (number error) Zembrin
®
0.2 0.15 0.41 0.18
Placebo 0.5 0.22 0.33 0.17
Alert Zembrin
®
53.18 4.40 61.67 2.97 66.88 3.29
Placebo 53.84 4.12 61.42 2.97 62.84 3.29
Calm Zembrin
®
67.35 4.93 61.6 4.02 47.04 4.95
Placebo 66.4 4.47 61.3 4.01 45.50 4.95
Content Zembrin
®
58.5 2.83 60.99 1.23 59.44 1.75
Placebo 58.6 2.91 58.58 1.23 56.07 1.75
Abbreviation: SE, standard error.
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ET AL.
3.2.2
|
Stress induction
A trend toward a main effect of time on STAI(s) (F(2,14) ¼3.49,
p ¼0.059) and HR (F(2,14) ¼3.325, p ¼0.06) coupled with a main
effect of time on VA(a) (F(3,21) ¼3.23, p ¼0.043) confirmed stress
induction.
3.2.3
|
Effects of treatment
STAI (state): ANCOVA revealed a treatment time interaction
(F(1,17) ¼8.05, p ¼0.011). Post hoc analysis revealed a difference at
prestress (p ¼0.009, d ¼1.01) with anxiety level significantly lower
in the Zembrin
®
group (Figure 2).
VAa scale: ANCOVA revealed a treatment time interaction
(F(2,34) ¼3.28, p ¼0.05). Post hoc analysis revealed a difference at
prestress (p ¼0.024, d ¼1.11) with anxiety level being significantly
lower in the Zembrin
®
group (Figure 2).
HR: ANCOVA revealed a treatment time interaction (F(1,17) ¼
6.08, p ¼0.025). The pattern of results demonstrates a physiological
response to the stressor (increased HR) in placebo but not Zembrin
®
group (Figure 3).
4
|
DISCUSSION
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. In the current studies, stress
induction was confirmed in study 1 as participants reported
increased subjective experience of alertness and decreased feelings
of calmness following completion of the MTF (see Wetherell &
Carter, 2014) and in study 2 by participants reporting elevated
feelings of anxiety/stress and increased HR following completion of
the simulated public speech task. With regard to the therapeutic
properties of Sceletium tortuosum (Zembrin
®
), study 1 failed to show
any effect of treatment on feelings stress or memory performance;
however, study 2 demonstrated that Sceletium tortuosum (Zembrin
®
)
ameliorated the anticipatory increase in subjective feelings of anxiety
associated with the anticipated onset of a stressor and ameliorated
increases in HR during a stressor.
The lack of an anxiolytic effect in study 1 and on subjective
measures at the mid and poststress testing points in study 2 could
most parsimoniously be explained by our protocol. For example,
despite both protocols inducting elevated feelings of stress, it could
be that the stressor was too “mild” to allow a treatment effect to be
observed in those subjective selfreport measures. For example, it is
clear that our participants did not rate their reported anxiety
greater than the halfway point on the anxiety scale nor score more
than half on the STAI(s). However, it should be noted that an effect
was observed in the physiological measure. With regard to a lack of
effect on cognitive function, we could interpret this result as the
first evidence to suggest that Sceletium tortuosum (Zembrin
®
) has no
impact on nonexecutive memory processing in healthy volunteers;
however, we would advise some caution with this, as our primary
aim was to investigate the anxiolytic properties and our research
design was tailored toward this question and it is possible that again
our lack of effect here can also be due to differences between our
study and previous studies. For example, Terburg et al. (2013) uti-
lized a longer treatment regime, tested a different population (older
adults), and assessed different cognitive functioning (i.e., executive
functioning). We recommend that future studies consider using
protocols that elicit stronger stress responses, for example, adding
critical social evaluation to the MTF (e.g., Wetherell et al., 2017), or
running a longer, and more challenging social evaluation paradigm
TABLE 2Study 2: Means and SE for
each outcome measure at baseline and
each measurement point postdose
Baseline Prestress Midstress Poststress
Mean SE Mean SE Mean SE Mean SE
STAI (trait) Zembrin
®
39 2.75
Placebo 40.25 2.25
STAI (state) Zembrin
®
30.58 2.06 33.96 2.81 37.82 2.22
Placebo 35.38 2.20 44.43 3.48 35.88 2.75
Anxiety scale Zembrin
®
2.25 0.39 3.25 0.48 4.42 0.59 4.25 0.46
Placebo 3.63 0.885 4.61 0.6 4.99 0.74 3.49 0.57
HR (bpm) Zembrin
®
87.1 5.19 91.8 2.09 90.5 2.27
Placebo 87.52 5.63 87.09 2.57 93.85 2.78
GSR Zembrin
®
0.74 0.007 0.73 0.002 0.71 0.002
Placebo 0.71 0.88 0.75 0.002 0.74 0.002
Note: HR and GSR is average data at baseline (5 min), prestress (30 min), and midstress (5 min).
Abbreviations: GSR, galvanic skin response; HR, heart rate; SE, standard error; STAI, State–Trait
Anxiety Inventory.
REAY ET AL.
-
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to further our understanding of the anxiolytic effects of Sceletium
tortuosum (Zembrin
®
). Future studies should also use more
comprehensive cognitive assessment to investigate whether Scele-
tium tortuosum (Zembrin
®
) has any task/cognitive domain specificity
of effect.
We conclude that a single 25 mg dose of Sceletium tortuosum
(Zembrin
®
) can ameliorate subjective and physiological indicators of
stress/anxiety during a controlled laboratory stress protocol in young
healthy volunteers.
CONFLICT OF INTEREST
The authors have declared no conflict of interest.
ORCID
Jonathon Reay
https://orcid.org/0000-0002-8252-1218
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FIGURE 2 Means and standard
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Stress in this context was a simulated
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Visual Analogue Anxiety Scale. Asterisks
indicate significant group difference at
that time point
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(HR) at prestress and midstress. Stress in this context was a
simulated public speaking task. Prestress is the average HR during
the 30min absorption period; duringtest is the average HR during
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How to cite this article: Reay J, Wetherell MA, Morton E,
Lillis J, Badmaev V. Sceletium tortuosum (Zembrin
®
)
ameliorates experimentally induced anxiety in healthy
volunteers. Hum Psychopharmacol Clin Exp. 2020;e2753.
https://doi.org/10.1002/hup.2753
REAY ET AL.
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... In traditional folk medicine, leaves from the plant have been chewed or used in teas and implicated in the amelioration of thirst, staving hunger, and decreasing fatigue [2]. As of late, ZEM has been identified as a promising nutraceutical with potent anxiolytic and anti-depressant actions [3,4]. These actions are likely manifested through high mesembrine alkaloid concentrations within ZEM, which have been reported to alter central nervous system activity [5]. ...
... Investigations of ZEM treatment in humans have been primarily studied in the context of anxiety and mood [3,4,18]. Terburg et al. showed that ZEM treatment decreased anxiety-related amygdala activation and may diminish threat responsivity by amygdalahypothalamus decoupling [3]. ...
... Terburg et al. showed that ZEM treatment decreased anxiety-related amygdala activation and may diminish threat responsivity by amygdalahypothalamus decoupling [3]. Improvements in mood and sleep patterns, and reductions in anxiety, have also been reported in young healthy adults [4,18]. We are only aware of one investigation studying how ZEM supplementation influences responses to physical exercise. ...
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The purpose of this study was to investigate acute Zembrin® (Sceletium tortuosum) supplementation on muscle soreness, markers of muscle damage, mood, and exercise performance following unaccustomed resistance exercise. Untrained females (n = 16) were divided into two groups with a different three-day treatment regimen: (1) placebo (PL) and (2) Zembrin® (ZEM). During the initial visit, baseline perceived soreness, range of motion (ROM), mood state (profile of mood states (POMS) questionnaire), and plasma lactate dehydrogenase concentrations (LDH) were measured followed by the performance of an eccentric bicep curl protocol with their non-dominant arm. The total repetitions and rate of perceived exertion (RPE) were recorded throughout the exercise. The participants then supplemented with the corresponding treatment immediately following, the subsequent day, and 30 min prior to completing a 48 h follow-up visit. For the 48 h visit, all procedures were repeated and comparisons were drawn for perceived soreness, ROM, LDH, mood scores, total repetitions, and RPE. The findings indicate that short-term ZEM supplementation resulted in lower perceived soreness (p = 0.020) and a greater preservation of ROM (p = 0.028) at 48 h versus the PL group. Mood worsened from the baseline to 48 h regardless of the treatment (p = 0.043) but the decrements were exacerbated in the PL group compared with the ZEM group (p < 0.001). LDH levels (p = 0.019) and RPE (p = 0.008) were higher and total repetitions were lower (p < 0.001) at 48 h irrespective of the treatment. Although short-term dietary enrichment with ZEM did not alter the exercise performance or biomarkers of muscle damage, the current results suggest ZEM supplementation may be effective in reducing the markers of soreness and preserve mood following unaccustomed eccentric exercise.
... These products are sold as herbal teas, dietary supplements and other phytopharmaceutics. However, only some of these products have been scientifically investigated with the greatest quantity of information available for Zembrin R in terms of in vitro and in vivo pharmacological data (4,5) and more recently clinical studies focusing on this particular product as an anxiolytic and anti-depressant phytopharmaceutical (6)(7)(8)(9). In international markets, Sceletium products are classified as food supplements that are also sold in the complementary and alternative medicines sector. ...
... A one-way analysis of variance (ANOVA) for all quantitative data were performed using GraphPad Prism version 8 data did not conform to assumptions of normality, a nonparametric test using Kruskal-Wallis analysis was regarded as being most appropriate. Descriptive statistics using boxplots or stacked column charts were also employed to visualize the data. ...
Article
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The Sceletium genus has been of medicinal importance in southern Africa for millennia and Sceletium tortuosum (Aizoaceae), one of eight species in the genus has gained pharmaceutical importance as an anxiolytic and anti-depressant due to the presence of mesembrine alkaloids. S. tortuosum is used for the manufacture of herbal teas, dietary supplements and other phytopharmaceutical products. This study aimed to provide a metabolomic characterization of S. tortuosum and its sister species as these are not easy to distinguish using morphology alone. Plant samples were thus collected from various locations in the succulent Karoo (South Africa) and analyzed through liquid chromatography-mass spectrometry (LC-MS), using MS E fragmentation as a putative tool for chemical identities. Metabolomics-based analyses in combination with molecular networking were able to distinguish between the four species of Sceletium based on the presence of 4-(3,4-dimethyoxyphenyl)-4-[2-acetylmethlamino)ethyl]cyclohexanone ( m/z 334.2020; RT 6.60 min), mesembrine ( m/z 290.1757; RT 5.10 min) and 4'-O-demethylmesembrenol ( m/z 276.1597; RT 4.17 min). Metabolomic profiles varied according to the different localities and metabolites occurred at variable quantitative levels in Sceletium ecotypes. Molecular networking provided the added advantage of being able to observe mesembrine alkaloid isomers and coeluting metabolites (from the joubertiamine group) that were difficult to discern without this application. By combining high-throughput metabolomics together with global and feature based-molecular networking, a powerful metabolite profiling platform that is able to discern chemical patterns within and between populations was established. These techniques were able to reveal chemotaxonomic relationships and allowed for the discovery of chemical markers that may be used as part of monitoring protocols during the manufacture of phytopharmaceutical and dietary products based on Sceletium .
... The results of the study implied that Zembrin® lessened anxiety, improved some areas of cognitive function, and may have enhanced mood in healthy people (Dimpfel et al., 2017). Reay et al. (2020) investigated the anxiolytic properties of a single 25 mg dose of S. tortuosum standardized extract (Zembrin®) on induced anxiety/stress response in 20 healthy young volunteers. The study was a 2-part research design that employed a placebo-controlled and double-blind between-subject experimental approach. ...
... The results of the study implied that Zembrin® lessened anxiety, improved some areas of cognitive function, and may have enhanced mood in healthy people (Dimpfel et al., 2017). Reay et al. (2020) investigated the anxiolytic properties of a single 25 mg dose of S. tortuosum standardized extract (Zembrin®) on induced anxiety/stress response in 20 healthy young volunteers. The study was a 2-part research design that employed a placebo-controlled and double-blind between-subject experimental approach. ...
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.
... Post hoc analysis revealed a difference for the extract group at prestress (p = 0.024, d = 1.11) with the anxiety level being significantly lower in the Zembrin® group. No significant treatment effects were found on any other outcome measure [46]. The studies were underpowered and used a single dose of only 25 mg extract. ...
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.
... The results of the study implied that Zembrin® lessened anxiety, improved some areas of cognitive function, and may have enhanced mood in healthy people (Dimpfel et al., 2017). Reay et al. (2020) investigated the anxiolytic properties of a single 25 mg dose of S. tortuosum standardized extract (Zembrin®) on induced anxiety/stress response in 20 healthy young volunteers. The study was a 2-part research design that employed a placebo-controlled and double-blind between-subject experimental approach. ...
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 results showed levels of anxiety were inferior in the Zembrin ® group compared to the placebo group. Behavioral evidence demonstrated the efficacy of S. tortuosum (25 mg Zembrin ® ) as an anti-anxiolytic agent [68]. Fountain [69] conducted a preclinical model assay on chicks to determine the effectiveness against anxiety and depression of S. tortuosum plant extracts. ...
Article
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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.
... Post hoc analysis revealed a difference for the extract group at prestress (p = 0.024, d = 1.11) with the anxiety level being significantly lower in the Zembrin® group. No significant treatment effects were found on any other outcome measure [46]. The studies were underpowered and used a single dose of only 25 mg extract. ...
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.
... [88] A single dose of S. tortuosum was found to relieve stress/ anxiety in healthy volunteers. [89] In a group of healthy, young adults (aged between 20 and 35 years), it was proved that 8-day use of 25 mg/day S. tortuosum extract yielded ergogenic benefits in the cognitive domain. [90] S. tortuosum extract at the doses of 8 and 25 mg/day was well tolerated in healthy people for 3 months. ...
... [88] A single dose of S. tortuosum was found to relieve stress/ anxiety in healthy volunteers. [89] In a group of healthy, young adults (aged between 20 and 35 years), it was proved that 8-day use of 25 mg/day S. tortuosum extract yielded ergogenic benefits in the cognitive domain. [90] S. tortuosum extract at the doses of 8 and 25 mg/day was well tolerated in healthy people for 3 months. ...
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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.
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In order to understand psychobiological responses to stress it is necessary to observe how people react to controlled stressors. A range of stressors exist for this purpose; however, laboratory stressors that are representative of real life situations provide more ecologically valid opportunities for assessing stress responding. The current study assessed psychobiological responses to an ecologically valid laboratory stressor involving multitasking and critical evaluation. The stressor elicited significant increases in psychological and cardiovascular stress reactivity; however, no cortisol reactivity was observed. Other socially evaluative laboratory stressors that lead to cortisol reactivity typically require a participant to perform tasks that involve verbal responses, whilst standing in front of evaluative others. The current protocol contained critical evaluation of cognitive performance; however, this was delivered from behind a seated participant. The salience of social evaluation may therefore be related to the response format of the task and the method of evaluation. That is, the current protocol did not involve the additional vulnerability associated with in person, face-to-face contact, and verbal delivery. Critical evaluation of multitasking provides an ecologically valid technique for inducing laboratory stress and provides an alternative tool for assessing psychological and cardiovascular reactivity. Future studies could additionally use this paradigm to investigate those components of social evaluation necessary for eliciting a cortisol response.
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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.
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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.
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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.