Received: 27 January 2020
Revised: 13 June 2020
Accepted: 30 June 2020
Sceletium tortuosum (Zembrin
) ameliorates experimentally
induced anxiety in healthy volunteers
|Mark A. Wetherell
Department of Psychology, School of Social
Sciences, Humanities & Law, Teesside
University, Middlesbrough, UK
Department of Psychology, Stress Research
Group, Northumbria University, Newcastle‐
American Medical Holdings Inc., New York,
New York, USA
Jonathon Reay, Department of Psychology,
School of Social Sciences, Humanities & Law,
Teesside University, Middlesbrough TS13BX,
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
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
anxiety, anxiolytic, Sceletium tortuosum, stress, zembrin
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
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-
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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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Sceletium tortuosum on restraint‐induced anxiety in rats.
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
) 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
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
With regard to the anxiolytic effect of Zembrin
, two studies have
identiﬁed potential biological mechanisms of action, the ﬁrst demon-
to be a dual serotonin (5‐HT) transporter blocker and
selective inhibitor of phosphodiesterase‐4 (Harvey, Young, Viljoen, &
Gericke, 2011) and the second demonstrated a single 25 mg dose of
could reduce anxiety‐related 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
. The ﬁrst study also investigated two additional purported
properties―the 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.
Both studies utilized a placebo‐controlled, double‐blind, 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.
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).
Study 1: Multitasking framework
The multi‐tasking 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 performance‐driven 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).
Study 2: Simulated public speaking task
On the day of testing, participants were informed that they would
be completing a 5‐min public speech to outline why they would be
the most suitable applicant for a job of their choosing. Following a
2‐min 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.
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
16‐item 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 100‐mm 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 (NASA‐TLX; Hart & Staveland, 1988): The NASA‐TLX measures
six workload domains. Three of which reﬂect the respondents
perceived demands of the task (mental demand, physical demand,
However, numerous side effects were also reported for both doses.
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.
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and temporal demand), and three reﬂect the interaction between the
task and the respondent (effort, perceived performance, and
State–Trait Anxiety Inventory (STAI; Spielberger, 2010): A 40‐item
inventory split into two 20‐item 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 10‐point 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
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
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.
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 one‐way between group analysis of
Placebo data for the Bond–Lader was analyzed by one‐way 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).
One‐way ANOVA was utilized for each domain of the NASA‐TLX (see
Table 1 for means and SE).
FIGURE 1 Study protocol for study 1 and
study 2. Dosage ¼25 mg Sceletium tortuosum
) 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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Placebo data for the STAI(s), VAa scale, HR, and GSR were analyzed
by one‐way 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
PSS: No signiﬁcant difference between placebo and Zembrin
(F(1,18) ¼0.76, p ¼0.785).
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.
Effect of treatment
No treatment effects observed on any outcome measure.
STAI (trait): No difference between placebo and Zembrin
(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
‐ ‐ ‐ ‐ 61.5 4.40
Placebo ‐ ‐ ‐ ‐ 64.8 4.40
‐ ‐ ‐ ‐ 64.4 5.08
Placebo ‐ ‐ ‐ ‐ 63.3 5.08
‐ ‐ ‐ ‐ 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 ‐ ‐
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
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
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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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
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).
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 self‐report measures. For example, it is
clear that our participants did not rate their reported anxiety
greater than the half‐way 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 ‐ ‐
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
REAY ET AL.
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to further our understanding of the anxiolytic effects of Sceletium
). Future studies should also use more
comprehensive cognitive assessment to investigate whether Scele-
tium tortuosum (Zembrin
) has any task/cognitive domain speciﬁcity
We conclude that a single 25 mg dose of Sceletium tortuosum
) can ameliorate subjective and physiological indicators of
stress/anxiety during a controlled laboratory stress protocol in young
CONFLICT OF INTEREST
The authors have declared no conﬂict of interest.
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FIGURE 2 Means and standard
error (error bars) of self‐reported
anxiety on the STAI(s) and VAa at
prestress, midstress, and poststress.
Stress in this context was a simulated
public speaking task. STAI(s), State–Trait
Anxiety Inventory (state score); VAa,
Visual Analogue Anxiety Scale. Asterisks
indicate signiﬁcant group difference at
that time point
FIGURE 3 Means and standard error (error bars) of heart rate
(HR) at prestress and midstress. Stress in this context was a
simulated public speaking task. Prestress is the average HR during
the 30‐min absorption period; during‐test is the average HR during
the 5‐min simulated public speaking task
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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.
REAY ET AL.
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