Investigating the synergistic and modulatory effects of cannabidiol with levodopa and dietary protein in Parkinson’s disease
Main Article Content
Keywords
adjunctive therapy; cannabidiol (CBD); dietary protein; levodopa; neurodegenerative disorder; randomized clinical trial (RCT); UPDRS
Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disorder primarily managed with levodopa, which, despite its efficacy, is limited by long-term complications and dietary interactions. An 8-week randomized clinical trial (n = 96) was designed to assess cannabidiol (CBD) as an adjunct to levodopa, examining the efficacy of dietary protein intake. Participants were assigned to either levodopa monotherapy or levodopa plus CBD (300 mg/ day) and further stratified based on dietary protein control. Symptom severity was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). The CBD group demonstrated a significantly greater improvement in total UPDRS scores (mean reduction: 51.2 ± 4.5) compared to the levodopa-only group (36.4 ± 3.2). Within the CBD group, patients following a protein-controlled diet showed enhanced improvement (53.6 ± 4.1) compared to those without dietary control (48.9 ± 4.8; P < 0.05). Improvements were observed across motor (tremor, rigidity, bradykinesia) and nonmotor (depression, motivation, sleep) domains. CBD was well-tolerated, with only mild, transient side effects such as drowsiness and dry mouth. These findings suggest that CBD is a safe and effective adjunctive therapy for PD, capable of enhancing both motor and nonmotor symptom control. Additionally, the study also indicated that dietary protein management can influence therapeutic outcomes, underscoring the importance of integrated pharmacological and nutritional strategies in PD management. This study recommends a large-scale study to explore underlying mechanisms.
References
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Müller, T., 2020. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease. Expert Opinion on Drug Metabolism & Toxicology. 16(5): 403–414. https://doi.org/10.1080/17425255.2020.1750596
Müller, T., 2025. Clinical pharmacokinetics of levodopa and relevant add-on therapies for Parkinson’s disease. Expert Opinion on Drug Metabolism & Toxicology. 21(3): 279–288. https://doi.org/10.1080/17425255.2024.2428831
Müller, T., Gerlach, M., Hefner, G., Hiemke, C., Jost, W.H. and Riederer, P., 2024. Therapeutic drug monitoring in Parkinson’s disease. Journal of Neural Transmission. 131(10): 1247–1262. https://doi.org/10.1007/s00702-024-02828-5
Nord, M., 2017. Levodopa pharmacokinetics-from stomach to brain: A study on patients with Parkinson’s disease. Vol. 1567. Medical Dissertation. Department of Clinical and Experimental Medicine, Linköping University, Sweden.
Omotayo, O.P., Lemmer, Y. and Mason, S., 2024. A narrative review of the therapeutic and remedial prospects of cannabidiol with emphasis on neurological and neuropsychiatric disorders. Journal of Cannabis Research. 6(1): 14. https://doi.org/10.1186/s42238-024-00222-2
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Rusch, C., Flanagan, R., Suh, H. and Subramanian, I., 2023. To restrict or not to restrict? Practical considerations for optimizing dietary protein interactions on levodopa absorption in Parkinson’s disease. NPJ Parkinson’s Disease. 9(1): 98. https://doi.org/10.1038/s41531-023-00541-w
Schneider, S.A. and Obeso, J.A., 2014. Clinical and pathological features of Parkinson’s disease. Current Topics in Behavioral Neurosciences. 22: 205–220. https://doi.org/10.1007/7854_2014_317
Su, D., Cui, Y., He, C., Yin, P., Bai, R., Zhu, J., et al. 2025. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: Modelling study of Global Burden of Disease Study 2021. BMJ. 388: e080952. https://doi.org/10.1136/bmj-2024-080952
Suryadevara, U., Bruijnzeel, D.M., Nuthi, M., Jagnarine, D.A., Tandon, R. and Bruijnzeel, A.W., 2017. Pros and cons of medical cannabis use by people with chronic brain disorders. Current Neuropharmacology. 15(6): 800–814. https://doi.org/10.2174/1570159X14666161101095325
Tambasco, N., Romoli, M. and Calabresi, P., 2018. Levodopa in Parkinson’s disease: Current status and future developments. Current Neuropharmacology. 16(8): 1239–1252. https://doi.org/10.2174/1570159X15666170510143821
Teil, M., Al-Kassmy, J., Alsalmi, M., Al-Rawahi, B. and Huot, P., 2025. The on-going quest for a long-acting oral form of levodopa. Expert Opinion on Drug Metabolism & Toxicology. 20: 1–10. https://doi.org/10.1080/17425255.2025.2535177
The citation (Kammerer et al. (2022)) was added in-error. The correct reference is
Vimal, D., D’Souza, L.C., Rai, V., Lal, S., Sharma, A. and Gupta, S.C., 2023. Efficacy of cannabis and its constituents in disease management: Insights from clinical studies. Current Medicinal Chemistry. 30(2): 178–202. https://doi.org/10.2174/0929867329666220525124818
Wang, M., Wang, Y.-H., Wang, B., Avula, M.M., Radwan, A.S., Wanas, J., et al. 2017. Decarboxylation study of acidic cannabinoids: A novel approach using ultra-high-performance supercritical fluid chromatography/photodiode array–mass spectrometry. Cannabis and Cannabinoid Research. 2(1): 1–11. https://doi.org/10.1089/can.2016.0020
Wang, W., Rao, L., Wu, X., Wang, Y., Zhao, L., & Liao, X. (2021). Supercritical carbon dioxide applications in food processing. Food Engineering Reviews, 13(3), 570-591. DOI: 10.1007/s12393-020-09270-9
Widmann, A.-K., M. A., Wahl., D. R., Kammerer., & R., Daniels., (2022). Supercritical Fluid Extraction with CO₂ of Curcuma longa L. in Comparison to Conventional Solvent Extraction. Pharmaceutics, 14(9): 1943. https://doi.org/10.3390/pharmaceutics14091943
Xiang Q, Xiang Y, Liu Y, Chen Y, He Q, Chen T, Tang L, He B and Li J. (2024). Revealing the potential therapeutic mechanism of Lonicerae Japonicae Flos in Alzheimer’s disease: a computational biology approach. Front. Med. 11:1468561. doi: 10.3389/fmed.2024.1468561
Zhuo Y, Li WS, Lu W, Li X, Ge LT, Huang Y, Gao QT, Deng YJ, Jiang XC, Lan ZW, Deng Q, Chen YH, Xiao Y, Lu S, Jiang F, Liu Z, Hu L, Liu Y, Ding Y, He ZW, Tan DA, Duan D, Lu M. 2024. TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients. Mil Med Res, 11(1):48. doi: 10.1186/s40779-024-00550-7.
Alonso-Alconada, D., Álvarez, F. J., Goñi-de-Cerio, F., Hilario, E., & Álvarez, A. (2020). Cannabinoid-mediated modulation of oxidative stress and early inflammatory response after hypoxia–ischemia. International journal of molecular sciences, 21(4), 1283. https://doi.org/10.3390/ijms21041283
Behl, T., Kaur, G., Bungau, S., Jhanji, R., Kumar, A., Mehta, V., et al. 2020. Distinctive evidence involved in the role of endocannabinoid signalling in Parkinson’s disease: A perspective on associated therapeutic interventions. International Journal of Molecular Sciences. 21(17): 6235. https://doi.org/10.3390/ijms21176235
Belgers, V., Röttgering, J.G., Douw, L., Klein, M., Ket, J.C., van de Ven, P.M., et al. 2023. Cannabinoids to improve health-related quality of life in patients with neurological or oncological disease: A meta-analysis. Cannabis and Cannabinoid Research. 8(1): 41–55. https://doi.org/10.1089/can.2021.0187
Ben-Shlomo, Y., Darweesh, S., Llibre-Guerra, J., Marras, C., San Luciano, M. and Tanner, C., 2024. The epidemiology of Parkinson’s disease. The Lancet. 403(10423): 283–292. https://doi.org/10.1016/S0140-6736(23)01419-8
Bhunia, S., Kolishetti, N., Arias, A.Y., Vashist, A. and Nair, M., 2022. Cannabidiol for neurodegenerative disorders: A comprehensive review. Frontiers in Pharmacology. 13: 989717. https://doi.org/10.3389/fphar.2022.989717
Chagas, M.H.N., Zuardi, A.W., Tumas, V., Pena-Pereira, M.A., Sobreira, E.T., Bergamaschi, M.M., et al. 2014. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: An exploratory double-blind trial. Journal of Psychopharmacology. 28(11): 1088–1098. https://doi.org/10.1177/0269881114550355
Chang, B., Jiang, Y., Feng, C., Li, B., Mei, J., Niu, C. (2025). Effect of purine diet on prognosis of deep brain stimulation for Parkinson’s disease. Food Science and Human Wellness, 14(3), 9250066. https://doi.org/10.26599/FSHW.2024.9250066
Dach, J., Moore, E.A. and Kander, J., 2015. Cannabis extracts in medicine: The promise of benefits in seizure disorders, cancer and other conditions. Jefferson, NC: McFarland.
Dalla Verde, C., Jayanti, S., El Khobar, K., Stanford, J.A., Tiribelli, C., Gazzin, S. Understanding the Pre-Clinical Stages of Parkinson’s Disease: Where Are We in Clinical and Research Settings? Int. J. Mol. Sci. 2025, 26, 6881. https://doi.org/10.3390/ijms26146881
De Meijer, E.P.M., 2009. Cannabinoid profiling of Cannabis samples for purity analysis. Journal of Natural Products. Chapter 5, p. 89). Oxford University Press
Del-Bel, E., de Souza Lisbôa, S.F. and Gomes, F.V., 2024. Cannabidiol in neurology and psychiatry. Oxford: Elsevier. Vol. 177.
Feng H, Qiao QC, Luo QF, Zhou JY, Lei F, Chen Y, Wen SY, Chen WH, Pang YJ, Hu ZA, Jiang YB, Zhang XY, Zhou TY, Zhang XY, Yang N, Zhang J, Hu R. 2024. Orexin Neurons to Sublaterodorsal Tegmental Nucleus Pathway Prevents Sleep Onset REM Sleep-Like Behavior by Relieving the REM Sleep Pressure. Research (Wash DC). 30;7:0355. doi: 10.34133/research.0355.
Ferrer, I., 2011. Neuropathology and neurochemistry of nonmotor symptoms in Parkinson’s disease. Parkinson’s Disease. 2011(1): 708404. https://doi.org/10.4061/2011/708404
Flores-Sanchez, I. J. and Verpoorte, R., 2008. PKS activities and biosynthesis of cannabinoids and flavonoids in Cannabis sativa L. plants. Plant and Cell Physiology. 49(12): 1767–1782. https://doi.org/10.1093/pcp/pcn150
Grotewold, N. and Albin, R.L., 2024. Update: Descriptive epidemiology of Parkinson’s disease. Parkinsonism & Related Disorders. 120: 106000. https://doi.org/10.1016/j.parkreldis.2024.106000
Hazekamp, A., 2008. Review: Cannabis—From cultivar to chemovar. Drug Testing and Analysis. 4(7–8): 660–667. https://doi.org/10.1002/dta.407
Hodgson, P., Jordan, A., Sinani, C. and Charura, D., 2025. Examining the relationship between physical function and anxiety/depression in Parkinson’s. Brain and Behavior. 15(5): e70563. https://doi.org/10.1002/brb3.70563
Hu, E., Li, T., Li, Z., Su, H., Yan, Q., Wang, L., Li, H., Zhang, W., Tang, T., Wang, Y. 2023. Metabolomics reveals the effects of hydroxysafflor yellow A on neurogenesis and axon regeneration after experimental traumatic brain injury. Pharm Biol. 61(1):1054-1064. doi: 10.1080/13880209.2023.2229379.
Jiang, Y., Qi, Z., Zhu, H., Shen, K., Liu, R., Fang, C., et al. 2025. Role of the globus pallidus in motor and non-motor symptoms of Parkinson’s disease. Neural Regeneration Research. 20(6): 1628–1643. https://doi.org/10.4103/NRR.NRR-D-23-01660
Khor, S.P. and Hsu, A., 2007. The pharmacokinetics and pharmacodynamics of levodopa in the treatment of Parkinson’s disease. Current Clinical Pharmacology. 2(3): 234–243. https://doi.org/10.2174/157488407781668802
Kumar, L., Malhotra, M., Singh, A.P. and Singh, A.P., 2024. Comprehensive review on Parkinson’s disease: Insights into prevalence, pathophysiology, diagnosis, and multifaceted treatment approaches. Journal of Drug Delivery & Therapeutics. 14(6): 200–213. https://doi.org/10.22270/jddt.v14i6.6637
Lu, Q., Chen, Y., Liu, H., Yan, J., Cui, P., Zhang, Q., Liu, Y. (2020). Nitrogen-containing flavonoid and their analogs with diverse B-ring in acetylcholinesterase and butyrylcholinesterase inhibition. Drug Development Research, 81(8), 1037-1047. https://doi.org/10.1002/ddr.21726
Müller, T., 2020. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease. Expert Opinion on Drug Metabolism & Toxicology. 16(5): 403–414. https://doi.org/10.1080/17425255.2020.1750596
Müller, T., 2025. Clinical pharmacokinetics of levodopa and relevant add-on therapies for Parkinson’s disease. Expert Opinion on Drug Metabolism & Toxicology. 21(3): 279–288. https://doi.org/10.1080/17425255.2024.2428831
Müller, T., Gerlach, M., Hefner, G., Hiemke, C., Jost, W.H. and Riederer, P., 2024. Therapeutic drug monitoring in Parkinson’s disease. Journal of Neural Transmission. 131(10): 1247–1262. https://doi.org/10.1007/s00702-024-02828-5
Nord, M., 2017. Levodopa pharmacokinetics-from stomach to brain: A study on patients with Parkinson’s disease. Vol. 1567. Medical Dissertation. Department of Clinical and Experimental Medicine, Linköping University, Sweden.
Omotayo, O.P., Lemmer, Y. and Mason, S., 2024. A narrative review of the therapeutic and remedial prospects of cannabidiol with emphasis on neurological and neuropsychiatric disorders. Journal of Cannabis Research. 6(1): 14. https://doi.org/10.1186/s42238-024-00222-2
Peña-Zelayeta, L., Delgado-Minjares, K., Rojas, M.V., León-Arcia, K., Santiago-Balmaseda, A., Andrade-Guerrero, J., et al. 2025. Non-motor symptoms in Parkinson’s disease. Journal of Personalized Medicine. 15(5): 172. https://doi.org/10.20944/preprints202503.1395.v1
Peres, F. F., Lima, A. C., Hallak, J. E., Crippa, J. A., Silva, R. H., & Abílio, V. C. (2018). Cannabidiol as a promising strategy to treat and prevent movement disorders?. Frontiers in pharmacology, 9, 482. DOI: 10.3389/fphar.2018.00482
Rana, A.Q., Ahmed, U.S., Chaudry, Z.M. and Vasan, S., 2015. Parkinson’s disease: A review of non-motor symptoms. Expert Review of Neurotherapeutics. 15(5): 549–562. https://doi.org/10.1586/14737175.2015.1038244
Riederer, P., Strobel, S., Nagatsu, T., Watanabe, H., Chen, X., Löschmann, P.A., et al. 2025. Levodopa treatment: Impacts and mechanisms throughout Parkinson’s disease progression. Journal of Neural Transmission (Vienna). 132(6): 743–779. https://doi.org/10.1007/s00702-025-02893-4
Rinaldi, D., 2025. Motor and non-motor symptoms in advanced Parkinson’s disease: Current insights and future directions. Doctoral Thesis. Università degli Studi di Roma La Sapienza.
Rusch, C., Flanagan, R., Suh, H. and Subramanian, I., 2023. To restrict or not to restrict? Practical considerations for optimizing dietary protein interactions on levodopa absorption in Parkinson’s disease. NPJ Parkinson’s Disease. 9(1): 98. https://doi.org/10.1038/s41531-023-00541-w
Schneider, S.A. and Obeso, J.A., 2014. Clinical and pathological features of Parkinson’s disease. Current Topics in Behavioral Neurosciences. 22: 205–220. https://doi.org/10.1007/7854_2014_317
Su, D., Cui, Y., He, C., Yin, P., Bai, R., Zhu, J., et al. 2025. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: Modelling study of Global Burden of Disease Study 2021. BMJ. 388: e080952. https://doi.org/10.1136/bmj-2024-080952
Suryadevara, U., Bruijnzeel, D.M., Nuthi, M., Jagnarine, D.A., Tandon, R. and Bruijnzeel, A.W., 2017. Pros and cons of medical cannabis use by people with chronic brain disorders. Current Neuropharmacology. 15(6): 800–814. https://doi.org/10.2174/1570159X14666161101095325
Tambasco, N., Romoli, M. and Calabresi, P., 2018. Levodopa in Parkinson’s disease: Current status and future developments. Current Neuropharmacology. 16(8): 1239–1252. https://doi.org/10.2174/1570159X15666170510143821
Teil, M., Al-Kassmy, J., Alsalmi, M., Al-Rawahi, B. and Huot, P., 2025. The on-going quest for a long-acting oral form of levodopa. Expert Opinion on Drug Metabolism & Toxicology. 20: 1–10. https://doi.org/10.1080/17425255.2025.2535177
The citation (Kammerer et al. (2022)) was added in-error. The correct reference is
Vimal, D., D’Souza, L.C., Rai, V., Lal, S., Sharma, A. and Gupta, S.C., 2023. Efficacy of cannabis and its constituents in disease management: Insights from clinical studies. Current Medicinal Chemistry. 30(2): 178–202. https://doi.org/10.2174/0929867329666220525124818
Wang, M., Wang, Y.-H., Wang, B., Avula, M.M., Radwan, A.S., Wanas, J., et al. 2017. Decarboxylation study of acidic cannabinoids: A novel approach using ultra-high-performance supercritical fluid chromatography/photodiode array–mass spectrometry. Cannabis and Cannabinoid Research. 2(1): 1–11. https://doi.org/10.1089/can.2016.0020
Wang, W., Rao, L., Wu, X., Wang, Y., Zhao, L., & Liao, X. (2021). Supercritical carbon dioxide applications in food processing. Food Engineering Reviews, 13(3), 570-591. DOI: 10.1007/s12393-020-09270-9
Widmann, A.-K., M. A., Wahl., D. R., Kammerer., & R., Daniels., (2022). Supercritical Fluid Extraction with CO₂ of Curcuma longa L. in Comparison to Conventional Solvent Extraction. Pharmaceutics, 14(9): 1943. https://doi.org/10.3390/pharmaceutics14091943
Xiang Q, Xiang Y, Liu Y, Chen Y, He Q, Chen T, Tang L, He B and Li J. (2024). Revealing the potential therapeutic mechanism of Lonicerae Japonicae Flos in Alzheimer’s disease: a computational biology approach. Front. Med. 11:1468561. doi: 10.3389/fmed.2024.1468561
Zhuo Y, Li WS, Lu W, Li X, Ge LT, Huang Y, Gao QT, Deng YJ, Jiang XC, Lan ZW, Deng Q, Chen YH, Xiao Y, Lu S, Jiang F, Liu Z, Hu L, Liu Y, Ding Y, He ZW, Tan DA, Duan D, Lu M. 2024. TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients. Mil Med Res, 11(1):48. doi: 10.1186/s40779-024-00550-7.
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Oct 1, 2025
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Awan, W. R. ., Zia, A., Khan, A. ., Ullah, N., Binsaleh, A. Y., Al-Hoshani, N., Alqasem, A. A., Mashat, R. M., Halawani, I. F., & Alhomrani, M. (2025). Investigating the synergistic and modulatory effects of cannabidiol with levodopa and dietary protein in Parkinson’s disease. Italian Journal of Food Science, 37(4), 352-363. https://doi.org/15586/ijfs.v37i4.3244
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How to Cite
Awan, W. R. ., Zia, A., Khan, A. ., Ullah, N., Binsaleh, A. Y., Al-Hoshani, N., Alqasem, A. A., Mashat, R. M., Halawani, I. F., & Alhomrani, M. (2025). Investigating the synergistic and modulatory effects of cannabidiol with levodopa and dietary protein in Parkinson’s disease. Italian Journal of Food Science, 37(4), 352-363. https://doi.org/15586/ijfs.v37i4.3244