Abstract: Background and aims: Aframomum melegueta (A. melegueta) from the ginger family is appreciated for its pungent seeds widely used in African ethno-medicine. Among the several biological activities associated with the seed’s preparations, some preclinical studies suggest a set of neuroactive properties that have not been tested in humans to date. We performed a clinical trial to investigate the effects of A. melegueta seed extracts on anxiety, stress, mood, and sleep in healthy subjects with moderate anxiety levels. In vitro pharmacological assays targeting the endocannabinoid, serotoninergic, and GABAergic systems were conducted to elucidate the underlying mechanism of action.
Methods: A. melegueta standardized to 10% total vanilloids (primarily 6-gingerol, 6-shogaol, and 6-paradol) was obtained after hydroalcoholic extraction and the spray-drying microencapsulation process. Subjects consumed 50, 100, or 150 mg of the extract daily for two days. A set of validated psychometric test questionnaires was collected before and 48h after the first intake. A. melegueta extract interaction with canonical endocannabinoid receptors (hCB1R and hCB2R), the serotonin receptor (5HT1AR) and gamma-aminobutyric acid receptor (GABAA1R) was evaluated by the radioligand binding assay. Additionally, receptor functional assays and enzyme inhibition assays were conducted to test the extract’s functional activity on the non-canonical endocannabinoid receptor (TRPV1) and the cannabinoid fatty-acid amide hydrolase enzyme (FAAH), respectively.
Results: In vitro pharmacological tests showed that the A. melegueta extract activated TRPV1, modulated both hCB2R and 5HT1AR and inhibited FAAH, which is the enzyme primarily responsible for hydrolyzing endogenous anandamide. After a 48h intake period, the extract significantly reduced anxiety and tension related to stress, improved overall mood, and enhanced sleep quality in the participants at doses ranging from 50 to 150 mg, with no reported side effects.
Conclusions: This study supports the potential of the A. melegueta extract for anxiety reduction, mood improvement, stress mitigation, and sleep enhancement. The in vitro tests suggest that the extract’s primary mechanism of action may involve the inhibition of FAAH, which is a key target in anxiety management.
This study found that, after three days of ingestion of VAN, positive results were observed in anxiety reduction, stress alleviation, mood elevation, and sleep quality improvement. These effects may help to effectively break the negative feedback loop in the stress–mood–sleep cycle. The results also revealed a dose-dependent enhancement in sleep quality, even with a single dose. Notably, these improvements in sleep quality were achieved without any adverse effects or sedative properties.
Keywords: Vanizem - Aframomum melegueta; botanical extract; endocannabinoid system; phytocannabinomimetics; stress; anxiety; vanilloid compound; paradol.

Aframomum melegueta Seed Extract’s Effects on Anxiety, Stress, Mood, and Sleep: A Randomized, Double-Blind, Pilot Clinical Trial, Rubén Pérez-Machín, Tanausú Vega-Morales, Carlos Elvira-Aranda, Loreto Lledó-Rico, María José Gomis-Gomis and Laura López-Ríos - Pharmaceuticals 2025, 18, 278

Background This study was designed to evaluate the beneficial effects of a botanical extract combination containing soy isoflavone extract (100mg), Aframomum melegueta seed dry extract (50 mg), and Punica granatum skin dry extract (100mg) on health-related Quality of Life in healthy Spanish menopausal women with hot flashes, anxiety, and depressive symptoms using the validated Cervantes Scale.
Methods and results Fifty-seven outpatient women (45–65 years) with menstrual problems associated with climacteric syndrome were enrolled from April 2018 to April 2019 in the context of a prospective, placebo-controlled, double-blind study. Women were randomized to receive treatment with either the botanical combination (250 mg daily divided into two doses) or placebo for eight weeks. At the beginning and end of the study, health-related Quality of Life was assessed using the Cervantes Scale. Subjects treated with the botanical extract, compared to subjects in the placebo group, showed a significant improvement in the Global health-related Quality of Life score (38% [11.3–50.0]% vs. 18.8% [0–37.7]%; P = 0.04) on the Cervantes Scale and, specifically, in the menopause and health domain (13.6% [0–45.4]% vs. 40.7% [20.6–61.0]%; P = 0.05). By contrast, there were no significant changes in the psychic, sexuality, and couple relationship related domains of the Cervantes Scale. Patients who concluded the study did not report substantial side effects.
Conclusion Short-term intake of the botanical combination improved the Global Quality of Life of climateric women, according to the Cervantes Scale. Since this is a pilot trial, results should be analysed with caution.
Trial registration NCT04381026;ClinicalTrial.gov (retrospectively registered).
Influence of a new botanical combination on quality of life in menopausal Spanish women: Results of a randomized, placebo-controlled pilot study - Laura Lo´ pez-Rı´os, Miguel A. Barber, Julia Wiebe, Rube´n P. Machı´n, Tanausu´ Vega- Morales, Ricardo Chirino, PLOS ONE / https://doi.org/10.1371/journal.pone.0255015 July 21, 2021

Aframomum melegueta roscoe K. Schum belongs to the ginger family, Zingiberaceae, commonly found in the coastal regions of Africa. AM is cultivated essentially for its valuable seed, which earned it the name “grain of paradise,” indicating its high value as a spice and medicine (Iwu et al., 1999). The seed is extensively used in ethno-medicine for a variety of ailments. It possesses active constituents with several biological activities, especially against inflammation and infectious diseases (Iwu et al., 1999). Studies have shown that the seeds of AM might turn out to be a source of medicines for health promotion and disease control (Dybas / Raskin, 2007; Umukoro / Ashorobi, 2008). In this chapter, the cultivation, applications to health and disease prevention, and adverse effects of Aframomum melegueta seeds are described.
Therapeutic Effects of Grains of Paradise (Aframomum melegueta) Seeds - Solomon Umukoro, Aderemi Caleb Aladeokin - Nuts & Seeds in Health and Disease Prevention. DOI: 10.1016/B978-0-12 -375688-6.10064-7

Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.
Neurobiological Interactions Between Stress and the Endocannabinoid System Maria Morena, Sachin Patel, Jaideep S Bains and Matthew N Hill, Neuropsychopharmacology Reviews (2016) 41, 80–102; doi:10.1038/npp.2015.166; published online 8 July 2015