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

The physiological actions of GLP-1 extend far improved formulations to reduce side effects, and
beyond glucose regulation. Its ability to enhance insulin innovative delivery systems, such as transdermal patches or
secretion, suppress glucagon release, and regulate appetite advanced oral technologies. Furthermore, the exploration
underscores its systemic importance in maintaining energy of combination therapies that enhance the efficacy of
balance and metabolic health. The therapeutic exploitation GLP-1RAs while reducing required doses holds promise
of these pathways through GLP-1R agonists (GLP-1RAs) for mitigating adverse effects and lowering costs, thereby
has revolutionized the treatment of T2DM and obesity, improving accessibility.
while ongoing research continues to uncover its broader
roles in cardiovascular and neurological health. 22 5. Potential development of P. harmala
extract to stimulate GLP-1 systemically
4. Present therapeutic applications of
GLP-1: Overview and challenges The therapeutic potential of P. harmala in enhancing
GLP-1 levels has been primarily explored in the context of
GLP-1RAs have revolutionized the management of T2DM brain research, particularly its effects on the hippocampus.
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and obesity, offering significant benefits in glycemic control, Translating these findings to systemic applications presents
weight management, and cardiovascular risk reduction. a promising avenue for metabolic disease management,
Agents, such as semaglutide, liraglutide, and dulaglutide such as T2DM and obesity. Studies have demonstrated
mimic the physiological effects of endogenous GLP-1 by that the bioactive alkaloids harmine and harmaline in
enhancing insulin secretion, suppressing glucagon release, P. harmala play pivotal roles in modulating molecular
and delaying gastric emptying, leading to improved blood mechanisms critical for GLP-1 stimulation. These
5,7
glucose levels and weight loss. Semaglutide, in particular, mechanisms include the activation of the Akt/GLUT4
has emerged as a model GLP-1RA due to its long-acting pathway, which enhances glucose uptake by promoting
profile and once-weekly administration, which improve Akt phosphorylation at serine 473 and increasing GLUT4
therapeutic efficacy and patient compliance. Landmark translocation. Furthermore, P. harmala significantly
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trials such as SUSTAIN and STEP have demonstrated its reduces oxidative stress by activating Nrf2, a master
efficacy in reducing Hemoglobin A1c, achieving substantial regulator of antioxidant responses, thereby increasing
weight loss, and providing cardioprotective benefits by glutathione levels and reducing lipid peroxidation. This
lowering the incidence of major adverse cardiovascular antioxidant effect creates a conducive environment for
events (MACE) in high-risk populations. Despite these GLP-1 synthesis and secretion. In addition, P. harmala
transformative outcomes, the clinical use of GLP-1RAs exhibits potent anti-inflammatory effects by mitigating
faces several challenges that hinder their widespread GSK-3β activity and reducing beta-amyloid accumulation,
adoption. 24
thereby alleviating neuroinflammation and cellular stress.
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One major challenge is the high cost of GLP-1RAs, These mechanisms, observed in the hippocampus, suggest
attributed to complex manufacturing processes and the that harmine and harmaline could similarly stimulate
substantial investments required for clinical development. GLP-1 secretion in enteroendocrine L-cells in the gut, the
This financial barrier disproportionately affects patients in primary site of GLP-1 synthesis. By activating glucose-
low- and middle-income countries, limiting access to these sensing pathways and protecting L-cells from oxidative
life-changing therapies. In addition, gastrointestinal side and inflammatory stress, P. harmala could enhance GLP-1
effects, such as nausea, vomiting, and diarrhea, are common, production and stability systemically. Moreover, the plant’s
particularly during the early phases of treatment, and may insulin-sensitizing effects, observed in brain studies,
lead to discontinuation for some patients. Rare but severe could extend to peripheral tissues, improving GLUT4
adverse events, including pancreatitis and gallbladder translocation and reducing insulin resistance. However,
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disease, further necessitate careful patient selection and challenges remain in translating these findings into
monitoring. The injectable nature of most GLP-1RAs, such clinical applications, including the need for standardized
as semaglutide, poses another limitation, as injection- extracts to ensure consistent alkaloid content, elucidation
related discomfort or needle phobia can deter treatment of gut-specific pathways to confirm their therapeutic
adherence. While oral formulations of semaglutide have potential, and optimization of dosing to balance efficacy
been developed to address this issue, their slightly reduced and safety given the potential toxicity of P. harmala at high
bioavailability and efficacy compared to injectable forms doses. With antioxidant, anti-inflammatory, and GLP-1-
present additional clinical considerations. 25,26 enhancing properties, P. harmala holds significant promise
To address these challenges, ongoing research aims for systemic metabolic regulation and the development of
to develop cost-effective manufacturing techniques, novel therapies targeting GLP-1 pathways. 5,7,27

Volume 2 Issue 3 (2025) 62 doi: 10.36922/IMO025060009