Cannabinoids in Parkinson’s Disease

Cannabinoids in Parkinson’s Disease show promise in relieving motor symptoms such as tremors and rigidity, as well as improving non-motor aspects like anxiety and sleep disorders. Initial research also suggests neuroprotective potential.

Parkinson’s disease (PD) is a complex neurodegenerative disorder characterized by motor symptoms (tremor, rigidity, bradykinesia) and non-motor symptoms (sleep disturbances, cognitive impairment, mood disorders). Current treatments primarily focus on dopamine replacement therapies like levodopa, but these often lose efficacy over time and can cause motor fluctuations and dyskinesia. Moreover, they do not address the underlying neurodegenerative processes or the diverse array of non-motor symptoms. Therefore, there is a growing interest in exploring alternative therapeutic strategies, such as cannabinoids, that can target multiple pathways involved in PD pathogenesis and offer symptomatic relief.

The Endocannabinoid System and Parkinson’s Disease

The endocannabinoid system (ECS), consisting of cannabinoid receptors (CB1 and CB2), endogenous cannabinoids (e.g., anandamide and 2-AG), and their associated enzymes, plays a crucial role in maintaining homeostasis and modulating various physiological processes, including neurotransmission, inflammation, and cell survival. The ECS is widely distributed in brain regions affected by PD, such as the basal ganglia, substantia nigra, and striatum.

In PD, there is evidence of ECS dysfunction, characterized by alterations in endocannabinoid levels and changes in receptor expression. For example, reduced CB1 receptor expression has been observed in the brains of PD patients, while animal models of PD have shown altered levels of anandamide and 2-AG. These alterations in the ECS may contribute to the pathophysiology of PD, including neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction.

Therapeutic Potential of Cannabinoids in PD

Cannabinoids, both plant-derived (e.g., THC, CBD, CBG) and synthetic, interact with the ECS and other receptor systems (e.g., TRPV1, PPAR, dopamine, glutamate, GABA) to modulate various physiological processes relevant to PD.

  • Motor Symptoms: Cannabinoids have shown potential in improving motor symptoms in PD. For instance, THC, through its partial agonism of CB1 receptors, can enhance dopamine release and modulate basal ganglia circuits, potentially alleviating bradykinesia and rigidity. CBD has been shown to reduce L-DOPA-induced dyskinesia by modulating glutamate and adenosine signaling.
  • Non-Motor Symptoms: The anxiolytic, antidepressant, and sleep-improving properties of cannabinoids, particularly CBD, may offer relief for PD patients experiencing anxiety, depression, insomnia, and other sleep disturbances. Additionally, cannabinoids may improve cognition and quality of life by modulating neuroinflammation and promoting neurogenesis.
  • Neuroprotection: Several studies have demonstrated the neuroprotective potential of cannabinoids in PD. CBD, for instance, has been shown to reduce oxidative stress, inflammation, and apoptosis, thereby protecting neurons from damage and potentially slowing down disease progression.

Clinical Evidence

There are over one hundred published papers on the use od cannabis in PD. These include laboratorial, pre clinical and clinical studies, with 12 double-blind placebo controlled trials.

Recent clinical trials, while not demonstrating definitive disease-modifying effects, have shown promise for symptomatic relief in PD. For example, a 2024 randomized controlled trial (RCT) by Liu et al. reported significant improvements in sleep, cognition, and activities of daily living in PD patients treated with cannabinoids. Other RCTs have shown potential benefits in pain management (phase 1b study) and improvement in biochemical markers (CBDEP trial). A study focusing on CBD/CBG enriched extracts showed positive results for RBD, insomnia, anxiety, pain, and hallucinations in PD and Dementia with Lewy Bodies (DLB) patients.

Systematic reviews and meta-analyses have also supported the potential of cannabinoids in ameliorating various motor and non-motor symptoms. However, it’s important to note that the evidence base is still evolving and more research is needed to confirm these findings.

Adverse Effects and Safety Considerations

Adverse effects associated with cannabinoids are typically dose-dependent and vary depending on the specific cannabinoid and formulation. THC, at higher doses, can cause cognitive impairment, ataxia, dysphoria, and dependence. These effects can be mitigated by using cannabis chemotypes with higher CBD content or by using CBG-dominant formulations. High-dose CBD may cause drowsiness and dizziness in some individuals.

Future Directions

While the current evidence for cannabinoids in PD is encouraging, further research is needed to determine optimal doses, formulations, and long-term effects. Future studies should focus on identifying specific PD subgroups that may benefit most from cannabinoid therapy, exploring the potential of combining cannabinoids with existing PD medications, and elucidating the precise mechanisms underlying cannabinoid actions in PD.

Cannabinoids hold promise as a potential therapeutic avenue for PD, offering symptomatic relief and potential neuroprotection. Further research is needed to establish their efficacy, safety, and optimal use in clinical practice. However, the existing evidence suggests a potential role for cannabinoids in managing PD symptoms and improving patients’ quality of life.

References

  • Costa AC, Joaquim HPG, Pedrazzi JFC, Pain AO, Duque G, Aprahamian I. Cannabinoids in Late Life Parkinson’s Disease and Dementia: Biological Pathways and Clinical Challenges. Brain Sci. 2022 Nov 22;12(12):1596. doi: 10.3390/brainsci12121596. PMID: 36552056; PMCID: PMC9775654.
  • Costa, Flavio Henrique & Oliveira, Simone & Spitz, Mariana & Rydz, Eduardo & Micheli, Gabriel & Tanaka, Elio & Ebner, Brian & Gladstone, Jaron & Lees, Andrew. (2022). Parkinson’s Disease and Dementia with Lewy Bodies, Patients Under Treatment with Standardized Extracts Enriched in Cannabidiol and Cannabigerol: Descriptive Observations in Preparation for a Phase 2a Clinical Trial. 14. 1-15. 10.31080/ecne.2022.14.01023. 
  • Di Luca DG, Gilmour GS, Fearon C, Swinkin E, Freitas E, Kuhlman G, Fox SH, Mestre T. A Phase Ib, Double Blind, Randomized Study of Cannabis Oil for Pain in Parkinson’s Disease. Mov Disord Clin Pract. 2023 May 8;10(7):1114-1119. doi: 10.1002/mdc3.13754. PMID: 37476317; PMCID: PMC10354611.
  • Junior NCF, Dos-Santos-Pereira M, Guimarães FS, Del Bel E. Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson’s Disease and L-DOPA-Induced Dyskinesia. Neurotox Res. 2020 Jan;37(1):12-29. doi: 10.1007/s12640-019-00109-8. Epub 2019 Oct 22. PMID: 31637586.
  • Kanjanarangsichai A, Mitarnun W, Mitarnun W, Pangwong W, Laoharattanahirun N, Kajornrith W, et al. Cannabidiol-enriched cannabis extraction product in Parkinson’s disease: A randomized, double-blind, and placebo-controlled trial in Buriram Hospital. J Neurosci Rural Pract 2022;13:663-8.
  • Liu, Y., Bainbridge, J., Sillau, S., Rajkovic, S., Adkins, M., Domen, C.H., Thompson, J.A., Seawalt, T., Klawitter, J., Sempio, C., Chin, G., Forman, L., Fullard, M., Hawkins, T., Seeberger, L., Newman, H., Vu, D. and Leehey, M.A. (2024), Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson’s Disease: A Randomized Trial. Mov Disord, 39: 863-875. https://doi.org/10.1002/mds.29768
  • Patel RS, Kamil S, Shah MR, Bhimanadham NN, Imran S. Pros and Cons of Marijuana in Treatment of Parkinson’s Disease. Cureus. 2019 Jun 3;11(6):e4813. doi: 10.7759/cureus.4813. PMID: 31403009; PMCID: PMC6682376.
  • Urbi B, Lee Y, Hughes I, Thorning S, Broadley SA, Sabet A, Heshmat S. Effects of cannabinoids in Parkinson’s disease animal models: a systematic review and meta-analysis. BMJ Open Sci. 2022 Dec 19;6(1):e100302. doi: 10.1136/bmjos-2022-100302. PMID: 36618606; PMCID: PMC9812814.

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