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Innovative Medicines & Omics Peganum harmala and GLP-1: A natural approach

The development of P. harmala as an accessible, The scalability and accessibility of P. harmala provide
low-cost natural therapeutic holds significant potential further advantages.
for addressing metabolic disorders by targeting
GLP-1 pathways. Unlike synthetic GLP-1RAs such as 6. Comprehensive evaluation of P. harmala
semaglutide, which are costly and require advanced in GLP-1 modulation
manufacturing processes, P. harmala offers a plant-based While the theoretical mechanisms underlying P. harmala’s
alternative with bioactive alkaloids, such as harmine impact on GLP-1 secretion are well-explored, experimental
and harmaline that could modulate similar molecular validation remains crucial. Pre-clinical evidence suggests
mechanisms. Semaglutide functions by directly mimicking that harmine and harmaline interact with intracellular
GLP-1, activating its receptor to promote insulin secretion, signaling pathways critical for GLP-1 synthesis and
reduce glucagon release, and delay gastric emptying, release. In particular, harmine has been shown to promote
thereby improving glycemic control and reducing appetite. pancreatic β-cell proliferation by inhibiting dual-specificity
However, its systemic distribution requires subcutaneous tyrosine-regulated kinase 1A, a key regulator of cellular
injection and advanced pharmacokinetic modifications to apoptosis. Moreover, its influence on incretin-secreting
32
extend its half-life, increasing production complexity and enteroendocrine L-cells remains under investigation,
cost. 28 emphasizing the need for targeted in vivo studies and
In contrast, P. harmala can indirectly enhance GLP-1 controlled clinical trials. Despite promising pre-clinical
levels and activity by targeting upstream pathways. insights, clinical trials assessing P. harmala’s efficacy in
Studies demonstrate that harmine and harmaline metabolic disorders are lacking. Future research must focus
stimulate GLP-1 secretion by modulating glucose-sensing on conducting randomized controlled trials to determine
mechanisms and reducing oxidative and inflammatory stress its therapeutic potential in managing insulin resistance,
in cells. These compounds activate the Akt/GLUT4 pathway, obesity, and T2DM. Establishing standardized dosing
which improves glucose uptake and metabolism, and regimens and long-term safety profiles will be essential for
enhances Nrf2-mediated antioxidant defenses, preserving translating these findings into clinical practice.
cellular integrity and functionality. Furthermore, harmine Harmine and harmaline are believed to modulate
and harmaline mitigate hyperinsulinemia by improving GLP-1 secretion through ATP-sensitive K (KATP)
+
insulin sensitivity, reducing serine phosphorylation of channels and calcium-mediated exocytosis. These
7
IRS-1, and enhancing downstream signaling pathways. alkaloids likely enhance intracellular Ca influx through
7,29
2+
These mechanisms make P. harmala a promising natural L-type voltage-gated calcium channels, which, in turn,
therapeutic for hyperinsulinemia and GLP-1 stimulation. trigger vesicular GLP-1 release. In addition, harmine’s
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To enhance the bioavailability and systemic distribution interaction with cAMP-response element-binding protein
of P. harmala alkaloids, nanotechnology offers an may potentiate GLP-1 gene expression by upregulating
innovative solution. Techniques such as encapsulating proglucagon transcription, reinforcing its role in incretin
harmine and harmaline in biodegradable nanoparticles hormone synthesis. High doses of P. harmala have been
7
or liposomes could improve their solubility, protect them associated with neurotoxic and hepatotoxic effects, largely
from enzymatic degradation in the gastrointestinal tract, attributed to excessive β-carboline alkaloid accumulation.
and allow for controlled release. This approach could In vivo toxicity studies reveal that harmine can induce
enable oral administration with enhanced absorption and mitochondrial dysfunction through oxidative stress-
targeted delivery to GLP-1-producing L-cells in the gut or mediated cytochrome c release, necessitating careful dose
pancreatic beta cells, mimicking the localized action of optimization. Future studies should aim to delineate the
semaglutide. therapeutic window for safe human consumption while
Moreover, P. harmala could be developed as an implementing nanoparticle-based drug delivery systems
oral supplement or capsule, with optimized doses of to mitigate toxicity risks. 34
standardized extracts. Pre-clinical studies suggest a dose Nanotechnology holds immense promise in improving
range of 150 – 200 mg/kg per day for achieving therapeutic the bioavailability of P. harmala-derived alkaloids.
effects in metabolic disorders. By comparison, Liposomal and polymeric nanoparticle formulations
30
semaglutide typically requires weekly doses of 0.5 – 1 mg can protect harmine and harmaline from enzymatic
subcutaneously. While semaglutide has a longer duration degradation, ensuring prolonged systemic circulation.
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of action due to its synthetic modifications, P. harmala could Encapsulation techniques utilizing polyethylene glycol
benefit from nanotechnology to achieve sustained release (PEG)-modified nanoparticles have demonstrated
and comparable efficacy with daily oral administration. increased cellular uptake and sustained release, facilitating

Volume 2 Issue 3 (2025) 63 doi: 10.36922/IMO025060009