Parkinson's disease (PD) is a neurodegenerative condition characterised by the death of dopaminergic neurons predominantly in the substantia nigra region of the brain and the accumulation of protein aggregates called Lewy bodies (Kouli et al., 2018). The primary clinical motor symptoms of this disease include bradykinesia, impaired gait, rigidity, resting tremor, and posture. It is also accompanied by non-motor symptoms such as sleep disturbances, anxiety, depression, apathy and cognitive defects. It commonly presents in older adults, and only a small percentage of cases occur in middle age which usually have an underlying genetic association. Latest data from the American PD Foundation estimated that over 10 million people suffer from PD worldwide, showing an increase of 81 % since 2000 (Organization, 2019; Ou et al., 2021). Published reports indicate that men are 1.5 times more likely to develop PD than women (Ou et al., 2021). PD can be properly diagnosed only after the core symptoms are evident and by this stage significant neuronal loss has already occurred.

There are currently no treatments which slow the progression of PD. The only effective current drug therapies are associated with restoring dopamine levels (Brooks, 2000). However, dopamine treatment is less effective as the disease progresses and there are adverse effects of long-term use (Rizek et al., 2016; Zahoor et al., 2018).

Products derived from Cannabis sativa L. plants have been proposed as a clinically promising therapy in PD. Cannabis plants produce a range of substances called phytocannabinoids and these substances have been proposed to have therapeutic benefit in treating PD. The two most abundant and well-studied phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the principal psychoactive constituent of cannabis. The psychoactive effects of THC are primarily mediated by interaction with cannabinoid receptors (Jones & Vlachou, 2020; Mechoulam & Gaoni, 1965). CBD is a nonpsychoactive constituent of cannabis and is the second most prevalent active ingredient (Razdan, 1986). CBD has been reported to have neuroprotective, antioxidant and anti-inflammatory activity and has antipsychotic, anxiolytic and analgesic uses (Brooks, 2000; Zahoor et al., 2018), which are relevant to the treatment of the underlying pathology of PD. A recent review of CBD studies verified that CBD provides a reduction in erratic movements, tremors, and anxiety in PD (Peres et al., 2018). In CBD clinical trials, patients with PD have shown significant improvements in mobility, communication, emotional well-being and quality of life (Goldenberg, 2008; Nguyen et al., 2022).

Although THC and CBD have a similar chemical structure, they interact with the human endocannabinoid system (ECS) differently. This review will focus on CBD. The ECS is comprised of endocannabinoids, (naturally occurring lipid neurotransmitters), cannabinoid receptors and endocannabinoid synthesis enzymes. CBD is a pleiotropic compound that acts on multiple targets, in the ECS it has been shown to interact with the cannabinoid receptors and also to influence the synthesis, degradation, and binding of endocannabinoids to these receptors. CBD however binds poorly to the endocannabinoid receptors and may in fact exert many of its effects independently of the ECS including via binding of other receptors, enzymes, and neurotransmitters (Atakan, 2012; Green et al., 2024). While the use of CBD in pre-clinical studies shows promise as a therapeutic agent, gaps remain in our knowledge of the mechanism of action and the risks associated with its use.

This review focuses on how CBD interacts with receptors and signalling molecules to influence key cellular pathophysiological processes relevant to PD. These pathophysiological processes include inflammation, oxidative stress, mitochondrial function, and neurotransmitter signalling. It is also important to determine if there are possible adverse effects of chronic or long-term use of CBD and this review will present the evidence for both acute and chronic effects of CBD.

The underlying pathological mechanisms which contribute to neuronal cell death in PD are multifactorial but primarily involve mitochondrial dysfunction and impaired autophagic and lysosomal processes (Rocha et al., 2018). Defects in these processes leads to increased oxidative stress, inflammation and misfolding and aggregation of proteins, with alpha synuclein the most abundant misfolded protein identified in PD (Abramov et al., 2020; Negi et al., 2024; Rocha et al., 2018; Wilson et al., 2023).

Mitochondrial dysfunction has long been identified as a key pathological process in PD and early evidence for this came from studies using the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP (Chen et al., 2022). In primates and rodents treatment with MPTP resulted in death of dopaminergic neurons and presentation of motor and non-motor symptoms of PD through selective inhibition of mitochondrial complex I. These experiments were substantiated by experiments using other Complex I inhibitors including paraquat and rotenone and genetic approaches which inhibited Complex I function directly in dopaminergic neurons. In all these cases a parkinsonism phenotype was evident. Mitochondrial complex I deficiency has also been detected in the substantia nigra pars compacta (SNpc) during autopsies of PD patients (Schapira et al., 1990).

Further evidence for mitochondrial dysfunction comes from the fact that many of the genes associated with genetic forms of PD are directly linked to mitochondrial function. These include PINK and PARKIN1, two proteins which play vital roles in mitochondrial quality control mechanisms (Pickrell & Youle, 2015; Quinn et al., 2020). Impairment of mitochondrial function ultimately leads to an increase in reactive oxygen species (ROS), a decrease in adenosine triphosphate (ATP) production and an increase in inflammatory markers (Pickrell & Youle, 2015). The production of ROS is exacerbated in dopaminergic neurons as dopamine metabolism itself can lead to production of ROS. The increased ROS production can cause oxidative damage to cellular lipids, proteins, and DNA.

A decrease in autophagic and lysosomal processes further compounds mitochondrial dysfunction as it impairs clearance of dysfunctional mitochondria (de la Mata et al., 2016). Impairments in clearance processes also leads to the accumulation of misfolded and dysfunctional proteins predominantly in discrete regions called Lewy bodies whose presence is a hallmark of PD (Wakabayashi et al., 2007). Alpha synuclein is the most abundant protein in Lewy bodies and the accumulation and misfolding of α-synuclein is central to PD pathology and is a mechanistic driver of neurodegeneration and symptom progression in PD. Post-mortem studies have confirmed the presence of α-synuclein-positive inclusions in the SNpc (Breydo et al., 2012; Negi et al., 2024; Xu et al., 2015) and mutations in the α-synuclein gene are associated with familial forms of PD. Furthermore, intracerebral injection of preformed α-synuclein fibrils have been shown to cause the spread and accumulation of pathological aggregates, dopaminergic neurodegeneration and Parkinson's-like Lewy pathology. The accumulation of Lewy bodies and protein aggregates resulted in progressive loss of dopaminergic neurons in the SNpc leading to reduced dopamine levels and motor deficits (Luk et al., 2012).

Neuroinflammation is another pathophysiological feature of PD (Qian et al., 2010; Wang et al., 2015). Neuronal cell death and aggregation of α-synuclein activate the brain's resident immune cells, microglia. When these microglia become activated in response to neuronal damage and dysfunction, levels of inflammatory mediators and proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 increase, ultimately exacerbating the neurodegenerative process. This creates a cycle where inflammation sustains microglial activation which contributes to neuronal death, and neuronal damage further fuels inflammation (Isik et al., 2023; McGeer et al., 1988; Nakagawa & Chiba, 2015). This has been validated in animal models of neuroinflammation created by directly injecting lipopolysaccharide (LPS) into the substantia nigra of rodents. This triggered robust microglial activation, leading to the release of pro-inflammatory cytokines and ROS. As a result, there was selective degeneration of dopaminergic neurons, effectively replicating the inflammatory and neurodegenerative aspects of PD. This inflammation-driven neuronal injury has also been implicated in non-motor symptoms of PD such as anxiety and cognitive dysfunction (Gao et al., 2002).

Disruptions in calcium homeostasis also contributes to neuronal death and the characteristic symptoms of PD (Kaur et al., 2023; Zhang et al., 2022). Dopaminergic neurons are particularly susceptible to disruptions in calcium signalling as this is essential for their pace making activities which enables them to fire action potentials rhythmically without synaptic output. Such pace-making activity is essential for maintaining basal dopamine levels. Disruption of calcium signalling can lead to intracellular calcium overload and subsequent mitochondrial dysfunction, increased oxidative stress and neuronal cell death (Verma et al., 2018). Neurons rely on several types of voltage-gated calcium channels (VGCCs) to regulate calcium levels. Cav1.3 L-type voltage-gated calcium channels are crucial for neuronal calcium homeostasis, mediating calcium influx in response to changes in membrane potential (Correa et al., 2023). Increased average basal calcium levels and an increased expression of Cav1.3 L-type voltage-gated Ca2+ channels have been observed in PD patients compared to controls. In PD, there is an increased reliance on Cav1.3 channels for Ca2+ influx and pacing activity of dopaminergic neurons (Sun, Zhang, et al., 2017). Cav1.3 channels allow for continuous Ca2+ influx important for regulating dopamine release however it also results in an increase in intracellular calcium levels and increased neurotoxicity.

Collectively, these identified and interconnected mechanisms drive the selective vulnerability of dopaminergic neurons in PD. Understanding the interplay between these mechanisms is essential for the development of effective strategies for PD.

Understanding how CBD can influence the core pathophysiological mechanisms of PD, is essential for evaluating its therapeutic potential and relevance to disease modification. This section will explore the existing scientific literature on how CBD can influence key drivers of PD pathology including mitochondrial dysfunction, oxidative stress, neuroinflammation and the clearance of aggregated proteins such as α-synuclein.

CBD has been shown to affect mitochondrial function via multiple mechanisms. Numerous studies have reported alterations in mitochondrial respiration following CBD exposure, although the magnitude and direction of these effects vary by cell type and concentration (Ryan et al., 2009). In a study by Valvassori and colleagues intraperitoneal injection of CBD (60 mg/kg per body weight) to adult male Wistar rats increased the activity of mitochondrial respiratory complexes in the tissues of the rat brain (Valvassori et al., 2013). Other neuronal studies used cell lines rather than whole animals and showed that low concentrations of CBD also increased mitochondrial respiration. In an oxygen–glucose-deprivation/reperfusion (OGD/R) model, mouse hippocampal neuronal cells that had been treated with 5 μM CBD showed increased mitochondrial respiration and increased glucose metabolism via the pentose phosphate pathway (Sun, Hu, et al., 2017). In a study by da Silva et al. (2018) neonatal iron exposure in rats induced significant mitochondrial dysfunction. These rats showed mitochondrial DNA deletions, reduced epigenetic regulation of mtDNA, lower mitochondrial ferritin, and impaired succinate dehydrogenase activity. Remarkably, a 14-day CBD treatment in adulthood reversed these changes by restoring mitochondrial ferritin levels, recovering succinate dehydrogenase activity and enhancing epigenetic modulation of mtDNA (da Silva et al., 2018).

In other studies, high concentrations of CBD in neuronal cells produced the opposite result, reducing mitochondrial respiration. In a study by Drummond-Main et al., using human neuroblastoma cells, low concentrations, 1–5 μM of CBD, mildly enhanced mitochondrial activity and increased basal respiration, whereas higher concentrations (≥10 μM) led to a reduction in mitochondrial membrane potential (ΔΨm), ATP production, and maximal respiratory capacity, indicating mitochondrial stress and early dysfunction (Drummond-Main et al., 2023).

Fišar et al., also reported a concentration dependent inhibitory effect of CBD in mitochondrial respiration in isolated pig brain mitochondria, notably through reduced activity of Complex I and II enzymes (Fišar et al., 2014). No beneficial effect of CBD was seen at low concentrations however increasing CBD concentrations led to decreasing activities of mitochondrial complexes.

Beyond respiration, CBD also modulates mitochondrial dynamics and biogenesis. In rodent models, CBD treatment caused an increase in the mitochondrial fission biomarker Dynamin-1-like protein (DNM1L) in the hippocampus compared to controls, whereas no effect on fusion biomarkers was evident. Fusion and fission are critical for maintaining mitochondrial integrity, cellular homeostasis, bioenergetic efficiency, and regulating organelle morphology. In a doxorubicin-induced model of cardiac mitochondrial dysfunction, pretreatment with CBD preserved the expression of mitochondrial biogenesis markers effectively preventing the drug induced decline in mitochondrial biogenesis (da Silva et al., 2014).

Oxidative stress, a critical mediator of dopaminergic neuron loss in PD, can also be influenced by CBD, however in a cell-type-specific manner. For example, LPS-induced oxidative stress led to reduced ROS in microglial cells after CBD exposure, whereas ROS increased in monocytes under the same conditions. The mechanism of this effect may be via scavenging of free radicals or it may be via reduction of the mitochondrial membrane potential which depolarises the mitochondria and increases ROS production (Borges et al., 2013). Furthermore, CBD has been shown to upregulate antioxidant defences, increasing the expression of cytoprotective genes such as superoxide dismutase (SOD) and glutathione peroxidase and preventing a reduction in the levels of microelements necessary for antioxidant activity (Atalay et al., 2019). CBD may additionally influence mitochondrial function via alterations in intracellular calcium signalling. It has been shown to increase cytosolic Ca2+ concentrations by promoting release from intracellular stores, primarily the mitochondria and endoplasmic reticulum (Olivas-Aguirre et al., 2019).

One hallmark of PD pathophysiology is the accumulation and aggregation of α-synuclein. CBD may mitigate this process by enhancing autophagic flux, as evidenced by increased levels of LC3-II and GFP-LC3-positive vesicles (these are markers of autophagosomes) (da Cruz Guedes et al., 2023; Erustes et al., 2025). In addition, CBD may also reduce α-synuclein expression via modulation of heat shock proteins (HSPs) which assist in protein folding and degradation thereby preventing protein aggregation (Dabir et al., 2004; Muhammad et al., 2022). In Caenorhabditis elegans expressing human α-syn, da Cruz Guedes et al. (2023) demonstrated that CBD treatment significantly decreased α-syn protein levels, as evidenced by reduced fluorescence intensity, and attenuated both dopaminergic neurodegeneration and behavioral deficits. They also showed that CBD reversed reserpine-induced α-syn accumulation and oxidative stress (da Cruz Guedes et al., 2023). This study supports CBD's role in reducing α-synuclein burden and protecting dopaminergic neurons.

Neuroinflammation, another driver of PD progression, is also attenuated by CBD. CBD inhibits cyclooxygenase enzymes COX-1 and COX-2, which catalyse the formation of inflammatory mediators such as prostaglandin E2. CBD also decreases pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, while elevating anti-inflammatory cytokines. It can promote apoptosis of T cells and decrease the activity of microglia cells to further reduce neuroinflammatory responses (Carvalho et al., 2019; Ruhaak et al., 2011). Additionally, CBD reduces pro-inflammatory cytokine levels, T cell proliferation and reduces migration and adhesion of immune cells (Lunn et al., 2006).

In summary, the evidence reviewed in this section strongly suggests that CBD holds promise in modulating key pathophysiological mechanisms underlying PD. Through its capacity to attenuate oxidative stress, preserve mitochondrial integrity, and influence protein homeostasis by attenuating misfolding and aggregation of α-synuclein, CBD demonstrates therapeutic potential for slowing disease progression. These effects directly target the cellular dysfunctions that contribute to dopaminergic neurodegeneration and disease progression. While further research is needed to fully characterize its molecular mechanisms, the current findings strongly support continued investigation of CBD as a candidate for disease-modifying intervention in Parkinson's disease.

Preclinical studies suggest potential neuroprotective, anti-inflammatory, and antioxidant benefits in laboratory and animal models (Table 1). Clinical trials specifically on CBD's effectiveness on motor and non-motor symptoms of PD patients however have yielded inconsistent results, with most showing improvements in motor scores, emotional regulation, and sleep, while others found no significant benefit or even potential negative impacts on cognitive function (Lim et al., 2024; Luz-Veiga et al., 2023; Mallah et al., 2020; Nahar et al., 2025). For example, an open-label dose-escalation study demonstrated that CBD administration led to improvement in motor symptoms and sleep quality, as measured by increased Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, and only mild adverse effects were reported. In contrast, in a double-blind exploratory trial, no significant changes in motor symptoms were found after CBD treatment (75 mg/day or CBD 300 mg/day) (Leehey et al., 2020; Urbi et al., 2022: Chagas et al., 2014). A randomized controlled trial by Hindocha et al. demonstrated that acute administration of CBD (16 mg) in healthy volunteers attenuated the memory-impairing effects of Δ9-THC. However, CBD independently produced a modest reduction in working memory performance, with the most pronounced effects observed on the Digit Span Backwards task (a sensitive measure of executive function). These findings suggest that even low doses of CBD may disrupt prefrontal cortex-mediated cognitive processes under certain conditions (Hindocha et al., 2015). Additional support for this effect comes from adolescent animal models. Jacobs et al. reported that repeated administration of CBD (20 mg/kg) in adolescent rats impaired recognition memory performance, as assessed using the novel object recognition task. Importantly, these cognitive deficits occurred in the absence of anxiety-like behaviours, indicating a targeted effect on memory function rather than a general behavioral suppression (Jacobs et al., 2016).

Most of the available preclinical studies investigating the effects of CBD in PD have demonstrated predominantly positive outcomes, with only a few reporting mild adverse effects such as diarrhea (Ewing et al., 2019; Skinner et al., 2020). The positive therapeutic effects include significant reductions in tremor and rigidity, along with improvements in sleep and overall quality of life. The number of comprehensive clinical trials conducted in PD however remains limited. The table presented herein provides some examples of CBD-PD specific clinical and preclinical studies.