Research Insights: Acute Effects of Sceletium tortuosum, a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus
This blog post is based on the article "Acute Effects of Sceletium tortuosum (Zembrin), a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus" by David Terburg, Supriya Syal, Lisa A Rosenberger, Sarah Heany, Nicole Phillips, Nigel Gericke, Dan J Stein, and Jack van Honk, published in Neuropsychopharmacology (2013, Volume 38, pp. 2708–2716). Read the full article here: Acute Effects of Sceletium tortuosum (Zembrin), a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus.
Sceletium tortuosum, a South African endemic plant, has a history of traditional use as a masticatory and in tincture form. This study explores the acute effects of a standardized extract (Zembrin) on brain activity related to threat processing, using pharmaco-fMRI in healthy participants.
Background on Kanna from the Research
Sceletium tortuosum has been traditionally used by San and Khoikhoi people and colonial farmers. Recent interest focuses on its alkaloids (mesembrenone, mesembrenol, mesembranol, mesembrine) and reported dual PDE4 inhibition and 5-HT reuptake inhibition. PDE4 regulates cAMP, with levels decreased in certain states, while 5-HT reuptake inhibitors are studied for mood effects. The combination may offer synergistic actions. Prior animal studies showed effects on restraint-induced behaviors, and case reports noted activity in clinical contexts. This is the first human brain imaging study on the extract.
Study Design and Methods
In a double-blind, placebo-controlled, cross-over design, 16 healthy right-handed participants (aged 18–21) received a single 25 mg dose of Zembrin or placebo, separated by 5–9 days. Scanning occurred 2 hours post-administration using fMRI.
Two tasks were used:
- Perceptual-load task: Assess amygdala reactivity to fearful faces under low/high perceptual load.
- Emotion-matching task: Match emotional faces (fearful/angry) or shapes, to analyze amygdala connectivity.
Amygdala BOLD responses and psychophysiological interaction (PPI) connectivity with hypothalamus, midbrain, brainstem, and prefrontal cortex were analyzed. Participants reported no side effects.
Key Findings
In the perceptual-load task, amygdala reactivity to fearful faces under low load was reduced after Zembrin compared to placebo.
In the emotion-matching task, amygdala-hypothalamus coupling was decreased after Zembrin. No significant changes in amygdala reactivity or other connectivity (midbrain, brainstem, prefrontal cortex) were observed.
These findings indicate attenuated threat responsivity in the amygdala and its subcortical connections.
Potential Mechanisms and Implications
The dual PDE4 and 5-HT reuptake inhibition may underlie reduced amygdala activity and connectivity, potentially influencing subcortical threat circuits. Amygdala involvement in threat detection and regulation supports these observations. The study provides initial evidence of brain effects in humans.
Limitations and Future Research
Limitations include small sample of healthy young participants, single low dose, and focus on threat circuitry. Future research could explore higher doses, repeated administration, diverse populations, and broader brain networks.
