Sceletium tortuosum and depression: mechanisms elucidated

We have previously shown a crude extract of Sceletium tortuosum (L.) N.E. Brown [Aizoaceae] to have anxiolytic effects in rats [1]. However, the exact mechanisms of this plant medicine have not been investigated comprehensively. Our aim was to elucidate its mechanisms of action in both the neuroendocrine and inflammatory immune systems, as both are implicated in depression. We recently reported that a high-mesembrine Sceletium extract acted as a monoamine releasing agent, and that the selective serotonin reuptake inhibition commonly ascribed to it, is a secondary effect only [2]. In the same study, mild inhibition of acetylcholinesterase and monoamine oxidase A (MAO-A) was also reported. Here we report differential inhibitory capacity for different Sceletium alkaloids on central enzymes, such as MAO-A, which informs greatly on the optimal formulation of Sceletium extracts aiming to treat depression. Also, in the peripheral compartment, we have shown the extract to inhibit adrenal steroidogenesis via inhibition of CYP17, 3βHSD and 17βHSD, suggesting beneficial therapeutic potential in conditions of stress and hypertension [3]. Here, we report that high-mesembrine Sceletium extract exerted cytoprotective effects on monocytes exposed to E. coli endotoxin (LPS) by correcting the < 60% loss in viability seen in untreated cells after LPS exposure (P < 0.0001, treatment effect). Monocytes exposed to the extract produced less pro-inflammatory cytokines (e.g., MCP-1, P < 0.005) over time, with a paralleled increase in anti-inflammatory signalling (e.g., IL-10, P < 0.05) – all of these in a dose-dependent manner. This effect, which would be beneficial in the context of chronic low grade inflammation leading to depression, did not hinder the monocytes from mounting a full acute response to LPS. We conclude that Sceletium may have dual benefit in the context of depression, by a) attenuating cytokine-induced depression and b) limiting psychologically-induced systemic low grade inflammation.

Acknowledgements: Dirk Coetzee is acknowledged for technical assistance.

Keywords: Inflammation, kanna, SSRI, monoamine, chronic low grade inflammation, serotonin.

References:

[1] Smith C. The effects of Sceletium tortuosum in an in vivo model of psychological stress. J Ethnopharmacol 2011, 133: 31 – 36

[2] Coetzee DD, López V, Smith C. High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor. J Ethnopharmacol 2016; 177: 111 – 116

[3] Swart AC, Smith C. Modulation of glucocorticoid, mineralocorticoid and androgen production in H295 cells by Trimesemine™, a mesembrine-rich Sceletium extract. J Ethnopharmacol 2016; 177: 35 – 45