Acute Effects of Sceletium Tortuosum
a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus
David Terburg1,2,5, Supriya Syal2,3,5, Lisa A Rosenberger¹, Sarah Heany², Nicole Phillips², Nigel Gericke4, Dan J Stein² and Jack van Honk1,2
²Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
³Department of Psychology, University of Toronto, Toronto, ON, Canada
4HG&H Pharmaceuticals (Pty) Ltd, Bryanston, South Africa
Correspondence: Dr D Terburg, Department of Psychology, Utrecht University, Heidelberglaan 2, Utrecht 3584 CS, The Netherlands, Tel: +31 30 253 3043, Fax: +31 30 253 4511, E-mail: firstname.lastname@example.org
5These authors contributed equally to this work.
Received 26 February 2013; Revised 22 July 2013; Accepted 22 July 2013
Accepted article preview online 1 August 2013; Advance online publication 21 August 2013
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 past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Sceletium) 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 Sceletium Tortuosum 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 Sceletium Tortuosum. 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 S. 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.
The South African endemic plant Sceletium tortuosum (L.) N.E. Br. (synonym Mesembryanthemum tortuosum L.), of the succulent family Mesembryathemaceae, has a long history of traditional use by San and Khoikhoi people as a masticatory and medicine (Smith et al, 1996) and later by colonial farmers as a psychotropic in tincture form (Pappe, 1868). Over the past 15 years, the plant has attracted increasing attention for its hypothesized applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating anxiety and depression in clinically anxious and depressed patients (Gericke and Viljoen, 2008). A recent in vivo study in rats demonstrated a positive effect of an extract of S. tortuosum on restraint-induced anxiety (Smith, 2011), and a small series of case reports described preliminary evidence for antidepressant and anxiolytic activity in patients suffering from major depression who were treated with tablets of milled S. tortuosum raw material (Gericke, 2001).
Materials and Methods
The active ingredient is a standardized and characterized aqueous ethanolic (purified water 30% V/V and ethanol 70% V/V, spray-dried onto a maltodextrin carrier) extract of the above ground material of a cultivated traditionally used selection of the South African plant S. tortuosum. Figure 1 shows the chemical structures of the four active alkaloids (mesembrenone, mesembrenol, mesembranol, and mesembrine), which were quantified by high pressure liquid chromatography (HPLC) analysis against validated analytical reference standards (Harvey et al, 2011). See Supplementary Information for a detailed description.
One participant performed below chance level (47% correct), which was >3 SDs below average (85%, SD=4), and was therefore excluded from analysis. A 2 × 2 × 2 repeated-measures ANOVA on the error rates with DRUG, LOAD, and EMOTION as within-subject factors revealed a significant effect of LOAD (F(1,14)=194.2, P<0.00001) but with no other main effects or interactions (all Ps>0.27). Reaction times revealed the same pattern: a significant effect of LOAD (F(1,14)=57.4, P<0.00001) but with no other main effects or interactions (all Ps>0.28; see Figure 2a).
|Hemisphere||Cluster size||Cluster P-value||Peak T-value||Coordinate|
|Perceptual load task:|
|High>low load (see also Figure 2b)|
|Placebo>Sceletium Tortuosum (low load: fear>neutral) (see also Figure 3b)|
|Emotion matching task:|
|Emotion>shape matching (see also Figure 4a)|
|Functional connectivity with amygdala: placebo>Sceletium Tortuosum|
|Main effect (see also Figure 4b)|
Abbreviations: ACC, anterior cingulate cortex; OFC, orbitofrontal cortex; PFC, prefrontal cortex; SMC, supplementary motor cortex.
All effects are whole-brain FWE-corrected with an extend threshold of 20 voxels unless stated otherwise. Coordinates refer to MNI space.
a FWE-corrected for ROI volume.
b FWE-corrected cluster-threshold with uncorrected cluster-defining threshold P<0.001.
The participant excluded from the PLT also scored near to chance level (56% correct) on the EMT, thus was also excluded here. No differences were found in performance for CONDITION or DRUG (emotion matching: 92% correct, SD=9, shape matching: 93%, SD=13).
In this pharmaco-fMRI study, we tested the effects of a single administration of Sceletium, a S. tortuosum extract that can be characterized as a dual PDE4 and 5-HT reuptake inhibitor (Harvey et al, 2011). Using two independent fMRI designs, we show that Sceletium compared with placebo administration reduces anxiety-related (Bishop et al, 2007) amygdala reactivity and attenuates amygdala–hypothalamus coupling. These results not only have importance as the first evidence on the dampening effects of Sceletium on the brain’s threat system but support further work on the clinical applicability of dual PDE4 and 5-HT reuptake inhibitors for the treatment of anxiety disorders and depression.
This study was made possible by funds from H.L. Hall and Sons, Ltd, South Africa and the Netherlands Organization of Scientific Research (Brain and Cognition Grant 056-24-010). NG is the Director, Medical and Scientific Affairs, of HG&H Pharmaceuticals (Pty) Ltd, the company that has developed the extract of Sceletium tortuosum. DJS has received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah, and Wyeth. The other authors declare no conflict of interest.
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