Zembrin®

One of the industry’s most advanced science programs

Zembrin has been the subject of one of the most extensive and forward-thinking clinical science programs in the nutraceutical industry.

Zembrin’s clinical program has traveled the journey from mechanistic understanding of Zembrin’s function to relevant clinical endpoints in humans, supporting consumer communications about improved well-being. The present indications for Zembrin, as a dietary supplement are to elevate mood, relieve stress and improve cognition (focus). Adjectives like “anti-stress, calmness, focused, serenity, motivated, energy, improves sleep” are often used to describe the experiential effects of Zembrin.

Human clinical research

fMRI study: Anxiety is characterized by hyper-responsivity to mild threats. In 2013, investigators from the University of Cape Town in South Africa, led by Dr. David Terburg, tested the effects of Zembrin in a pharmacologic study with corroboration by Functional Magnetic Resonance Imaging (fMRI)². The focus was to detect anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, sixteen (n=16) healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin. Follow-up connectivity analysis on the emotion matching task showed that amygdala–hypothalamus coupling was also reduced. These results demonstrated, for the first time, the effects of S. tortuosum on the threat circuitry of the human brain. Zembrin was shown to attenuate reactivity within the amygdala, the part of the brain that responds to threats. It provides supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity. 

² Terburg D, Syal S, Rosenberger LA, et al. Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus. Neuropsychopharmacology. 2013;38(13):2708-2716. doi:10.1038/npp.2013.183

Cognition study: Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cyclic AMP (cAMP) cascade signaling involving phosphorylated cAMP Response Element Binding Protein (CREB). To examine the neurocognitive effects of Zembrin and assess its safety and tolerability in cognitively healthy control subjects, researchers conducted a randomized, double-blind placebo-controlled crossover, proof-of-concept study of 21 healthy women and men (mean age 54.6 years.)³ Subjects received either 25 mg of Zembrin or matching placebo capsule once daily for 3 weeks. A battery of neuropsychological tests was used to assess the impact: 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. 

The CNS VitalSign® battery of tests assesses mood (i.e., fatigue, relaxed, tired, tense, upset, worried, alert, calm, hunger, thirst, anxious, stressed, happy) using visual analogues scales (VAS). It assesses cognition through computerized testing (stress through multitasking cognitive stressor FRAMEWORK; Cognitive tasks of attention, memory, and executive function). It assesses psychomotor function using biomarkers (blood pressure, cortisol, cortisol at bedtime) and a diary to track sleep quality, appetite, and adverse events. Secondary outcome measures were mood, assessed by the Hamilton Depression Rating Scale (HAM-D), safety, and tolerability.

Results: Zembrin significantly improved key cognitive domains, specifically cognitive set flexibility (𝑃 < 0.032) and executive function (𝑃 < 0.022), compared with the placebo group. Cognitive flexibility is the ability to shift attention between two or more tasks and the ability to adapt to rapidly changing directions and intelligently utilize information. It is necessary for decision-making, impulse control, and strategy formation. Executive function refers to exercising initiative, proper judgment, discipline, and the ability to operate in favor of an abstract reward; spontaneous ability to take action, and goal-directed behavior.

Positive changes in mood and sleep were also found, although changes in the HAM-D scores did not reach statistical significance, an expected outcome in a healthy, non-depressed population. Zembrin was well-tolerated. The authors concluded that the cognitive-enhancing effects of Zembrin were likely due to its impact on the PDE-4-cAMP-CREB cascade, offering potential applicability for support of cognitive function in older individuals.

³ Chiu S, Gericke N, Farina-Woodbury M, et al. Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia. Evid Based Complement Alternat Med. 2014;2014:682014. doi:10.1155/2014/682014

Single-dose EEG study: This study aimed to characterize the psychophysiological effects of a single dose of Zembrin of either 25 mg or 50 mg compared to placebo.⁴ The study employed a novel methodology called “EnkephaloVision”, developed by German brain researcher, Wilfried Dimpfel. The technology uses quantitative electroencephalogram (qEEG) software combined with eye-tracking, allowing for rapid detection and sensitive analysis of spectral EEG changes during cognitive and emotional challenges. 

Sixty subjects were given a series of mental tasks and exposed to emotional audio-visual clips before and 2 hours after intake of Zembrin or placebo. The tests comprised five cognitive challenges (Stroop-Test, Brain Teaser, Memory-Test, Picture Comparison, CPT-Test) and four emotional challenges (Emotion Pictures, Animal Videos, and Horror Videos). 

In comparison to the placebo, Zembrin induced enhanced increases in power of frontal delta, theta, alpha1, and alpha2 brain wave frequencies during several tasks. Increases in these frequencies in the frontal brain have been related to attention and memory. These results may represent a positive dose-dependent action of Zembrin on cognitive and emotional processes in the brain.

Six-week EEG study: The following year, the same research group did a follow-up study to measure the effects of 25 or 50 mg of Zembrin taken daily for 6 weeks compared to placebo.⁵ Sixty healthy male (n = 32) and female (n = 28) right-handed subjects between 50 and 80 years of age took part in the study. The EEG was recorded from 17 surface electrodes before and 1 hour 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 showed increases in delta activity during the 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. 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. Statistically significant improvement during performance of the arithmetic calculation test and number connection test was documented. The Hamilton anxiety score (HAM-A) revealed a statistically significant decrease (p = 0.03) after six weeks. The results indicate that in healthy people, Zembrin improves some aspects of cognitive function, decreases anxiety, and may enhance mood.

Single-dose anxiety study: In a two-part study, researchers used a double-blind, placebo-controlled, between-subject experimental design to investigate the effects of a single dose of Zembrin (25 mg) on induced stress/anxiety response in 20 young, healthy volunteers.⁶ To elicit feelings of stress/anxiety, participants completed 20 minutes of the multitasking framework in Part 1; and a 5-minute simulated public speaking task in Part 2. Part 1 measured subjective experiences of mood at baseline, pre-stress induction, and post-stress induction. Part 2 measured subjective experiences of anxiety and physiological indicators of stress (heart rate and galvanic skin response) at baseline, pre-stress induction, during stress induction, and post-stress induction. 

Results: No treatment effect was observed in Part 1; however, Part 2 revealed subjective anxiety levels to be significantly lower in the Zembrin group at the pre-stress induction point and a significant interaction between treatment and time on heart rate. Taken together, results indicate that a single dose of Zembrin can ameliorate induced stress/anxiety response in healthy volunteers, such as occurs before public speaking. The authors opine that the likely reason Part 1 failed to show a treatment effect is that the "stressor was too 'mild' to allow a treatment effect to be observed in those subjective self-report measures." It is also likely that daily administration, as opposed to a single dose, would produce a more pronounced effect.

⁴ Dimpfel W, Gericke N, Suliman S, Dipah GNC. Psychophysiological Effects of Zembrin® Using Quantitative EEG Source Density in Combination with Eye-Tracking in 60 Healthy Subjects. A Double-Blind, Randomized, Placebo-Controlled, 3-Armed Study with Parallel Design. Neurosci Med. 2016;7:114-32. doi:10.4236/nm.2016.73013

⁵ Dimpfel W, Gericke N, Suliman S, Dipah GNC. Effect of Zembrin® on Brain Electrical Activity
in 60 Older Subjects after 6 Weeks of Daily Intake. A Prospective, Randomized, Double-Blind, Placebo-Controlled, 3-Armed Study in a Parallel Design. World J Neurosci. 2017;7:140-71.

⁶ Reay J, Wetherell MA, Morton E, Lillis J, Badmaev V. Sceletium tortuosum (Zembrin®) ameliorates experimentally induced anxiety in healthy volunteers [published online ahead of print, 2020 Aug 6]. Hum Psychopharmacol. 2020;e2753. doi:10.1002/hup.2753