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: email@example.com
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.
- Anderson IM, McKie S, Elliott R, Williams SR, Deakin JF (2008). Assessing human 5-HT function in vivo with pharmacoMRI. Neuropharmacology 55: 1029–1037.
- Bar-Haim Y, Lamy D, Pergamin L, Bakermans-Kranenburg MJ, van IJzendoorn MH (2007). Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol Bull 133: 1–24.
- Baroncini M, Jissendi P, Balland E, Besson P, Pruvo J-P, Francke J-P et al (2012). MRI atlas of the human hypothalamus. Neuroimage 59: 168–180.
- Bigos KL, Pollock BG, Aizenstein HJ, Fisher PM, Bies RR, Hariri AR (2008). Acute 5-HT reuptake blockade potentiates human amygdala reactivity. Neuropsychopharmacology 33: 3221–3225.
- Bishop SJ (2008). Neural mechanisms underlying selective attention to threat. Ann NY Acad Sci 1129: 141–152.
- Bishop SJ, Jenkins R, Lawrence AD (2007). Neural processing of fearful faces: effects of anxiety are gated by perceptual capacity limitations. Cereb Cortex 17: 1595–1603.
- Bureau Y, Handa M, Zhu Y, Laliberte F, Moore CS, Liu S et al (2006). Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline. Neuropharmacology 51: 974–985.
- Cashman JR, Voelker T, Johnson R, Janowsky A (2009). Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression. Bioorg Med Chem 17: 337–343.
- Cherry JA, Davis RL (1999). Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol 407: 287–301.
- Davis M, Whalen PJ (2001). The amygdala: vigilance and emotion. Mol Psychiatry 6: 13–34.
- Del-Ben CM, Deakin JF, McKie S, Delvai NA, Williams SR, Elliott R et al (2005). The effect of citalopram pretreatment on neuronal responses to neuropsychological tasks in normal volunteers: an FMRI study. Neuropsychopharmacology 30: 1724–1734.
- Duman RS, Malberg J, Thome J (1999). Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 46: 1181–1191.
- Ekman P, Friesen W (1976) Pictures of Facial Affect. Consulting Psychologist Press: Palo Alto, CA, USA.
- Fisher PM, Price JC, Meltzer CC, Moses-Kolko EL, Becker C, Berga SL et al (2011). Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity. Biol Mood Anxiety Disord 1: 2.
- Fleischhacker WW, Hinterhuber H, Bauer H, Pflug B, Berner P, Simhandl C et al (1992). A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology 26: 59–64.
- Freitas-Ferrari MC, Hallak JE, Trzesniak C, Filho AS, Machado-de-Sousa JP, Chagas MH et al (2010). Neuroimaging in social anxiety disorder: a systematic review of the literature. Prog Neuropsychopharmacol Bol Psychiatry 34: 565–580.
- Fujita M, Hines CS, Zoghbi SS, Mallinger AG, Dickstein LP, Liow JS et al (2012). Downregulation of brain phosphodiesterase type IV measured with 11C-(R)-rolipram positron emission tomography in major depressive disorder. Biol Psychiatry 72: 548–554.
- Gericke N (2001). Clinical application of selected South African medicinal plants. Aust J Med Herbalism 13: 3.
- Gericke N, Viljoen AM (2008). Sceletium–a review update. J Ethnopharmacol 119: 653–663.
- Halene TB, Siegel SJ (2007). PDE inhibitors in psychiatry—future options for dementia, depression and schizophrenia? Drug Discov Today 12: 870–878.
- Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D et al (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science 297: 400–403.
- Harmer CJ, Goodwin GM, Cowen PJ (2009). Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry 195: 102–108.
- Harvey AL, Young LC, Viljoen AM, Gericke NP (2011). Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids. J Ethnopharmacol 137: 1124–1129.
- Kim MJ, Loucks RA, Palmer AL, Brown AC, Solomon KM, Marchante AN et al (2011). The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav Brain Res 223: 403–410.
- Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S et al (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25: 11489–11493.
- Korff S, Stein DJ, Harvey BH (2009). Cortico-striatal cyclic AMP-phosphodiesterase-4 signalling and stereotypy in the deer mouse: attenuation after chronic fluoxetine treatment. Pharmacol Biochem Behav 92: 514–520.
- Lavie N (1995). Perceptual load as a necessary condition for selective attention. J Exp Psychol Hum Percept Perform 21: 451–468.
- Li YF, Huang Y, Amsdell SL, Xiao L, O’Donnell JM, Zhang HT (2009). Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 34: 2404–2419.
- Manuck SB, Brown SM, Forbes EE, Hariri AR (2007). Temporal stability of individual differences in amygdala reactivity. AJ Psychiatry 164: 1613–1614.
- McCabe C, Mishor Z (2011). Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers. Neuroimage 57: 1317–1323.
- Murphy SE, Norbury R, O’Sullivan U, Cowen PJ, Harmer CJ (2009). Effect of a single dose of citalopram on amygdala response to emotional faces. Br J Psychiatry 194: 535–540.
- Nell H, Siebert M, Chellan P, Gericke N (2013). A randomized, double-blind, parallel-group, placebo-controlled trial of extract Sceletium tortuosum in healthy adults. J Altern Complement Med (in press).
- Otowa T, Kawamura Y, Sugaya N, Yoshida E, Shimada T, Liu X et al (2011). Association study of PDE4B with panic disorder in the Japanese population. Prog Neuropsychopharmacol Bol Psychiatry 35: 545–549.
- Pappe L (1868) Florae Capensis Medicae Prodromus. An Enumeration of South African Indigenous Plants used as Remedies by the Colonists of the Cape of Good Hope 3rd edn. W Brittain: Cape Town, South Africa.
- erez-Torres S, Miro X, Palacios JM, Cortes R, Puigdomenech P, Mengod G (2000). Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and[3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 20: 349–374.
- Pringle A, Browning M, Cowen PJ, Harmer CJ (2011). A cognitive neuropsychological model of antidepressant drug action. Prog Neuropsychopharmacol Bol Psychiatry 35: 1586–1592.
- Rock EM, Benzaquen J, Limebeer CL, Parker LA (2009). Potential of the rat model of conditioned gaping to detect nausea produced by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. Pharmacol Biochem Behav 91: 537–541.
- Rutten K, Van Donkelaar EL, Ferrington L, Blokland A, Bollen E, Steinbusch HWM et al (2009). Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology 34: 1914–1925.
- Saccomano NA, Vinick FJ, Koe BK, Nielsen JA, Whalen WM, Meltz M et al (1991). Calcium-independent phosphodiesterase inhibitors as putative antidepressants: [3-(bicycloalkyloxy)-4-methoxyphenyl]-2-imidazolidinones. J Med Chem 34: 291–298.
- Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20): 22–33.
- Silvert L, Lepsien J, Fragopanagos N, Goolsby B, Kiss M, Taylor JG et al (2007). Influence of attentional demands on the processing of emotional facial expressions in the amygdala. Neuroimage 38: 357–366.
- Smith C (2011). The effects of Sceletium tortuosum in an in vivo model of psychological stress. J Ethnopharmacol 133: 31–36.
- Smith MT, Crouch NR, Gericke N, Hirst M (1996). Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review. J Ethnopharmacol 50: 119–130.
- Terburg D, Morgan BE, Montoya ER, Hooge IT, Thornton HB, Hariri AR et al (2012). Hyper-vigilance for fear after basolateral amygdala damage in humans. Translational Psychiatry 2: e115.
- Tottenham N, Tanaka JW, Leon AC, McCarry T, Nurse M, Hare TA et al (2009). The NimStim set of facial expressions: judgments from untrained research participants. Psychiatry Res 168: 242–249.
- van Wingen G, Mattern C, Verkes RJ, Buitelaar J, Fernandez G (2010). Testosterone reduces amygdala-orbitofrontal cortex coupling. Psychoneuroendocrinology 35: 105–113.
- van Wingen GA, van Broekhoven F, Verkes RJ, Petersson KM, Bäckström T, Buitelaar JK et al (2008). Progesterone selectively increases amygdala reactivity in women. Mol Psychiatry 13: 325–333.
- Walker DL, Toufexis DJ, Davis M (2003). Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463: 199–216.
- Werenicz A, Christoff RR, Blank M, Jobim PF, Pedroso TR, Reolon GK et al (2012). Administration of the phosphodiesterase type 4 inhibitor rolipram into the amygdala at a specific time interval after learning increases recognition memory persistence. Learn Mem 19: 495–498.
- Ye Y, Jackson K, O’Donnell JM (2000). Effects of repeated antidepressant treatment of type 4A phosphodiesterase (PDE4A) in rat brain. J Neurochem 74: 1257–1262.