Cannabinoids and cognition in Parkinson’s disease: Insights from animal models and emerging evidence

Cannabinoids and cognition in Parkinson’s disease: Insights from animal models and emerging clinical evidence

Source / Quelle: https://www.sciencedirect.com/science/article/abs/pii/S0306452226001971

Abstract

Parkinson’s disease (PD) is a progressive, multisystem neurodegenerative disorder characterized not only by motor impairments but also by a broad spectrum of debilitating non-motor symptoms, including cognitive decline. The cognitive function depends on neuronal plasticity, which is tightly regulated by multiple signaling systems, among which the endocannabinoid system (ECS) plays a significant role. Over the past three decades, substantial evidence has accumulated regarding how endogenous cannabinoids, plant-derived cannabinoids, and pharmacological modulators of ECS signaling influence synaptic plasticity, neuronal excitability, and neuroinflammation — processes that are critical in PD pathophysiology.

This narrative review synthesizes experimental and clinical evidence on the effects of cannabinoid compounds on cognition in preclinical PD models and patients. Available clinical data are limited, heterogeneous, and often underpowered, with cognition frequently assessed as a secondary outcome. Observed variability in cognitive effects likely reflects differences in cannabinoid formulation, dose and treatment duration, study design, patient characteristics, and the use of heterogeneous cognitive endpoints across studies.

Cannabinoid-based interventions hold promise for preserving neural circuits and modulating cognitive function in PD; however, well-designed, mechanism-informed trials with standardized, domain-specific cognitive endpoints are essential before clinical recommendations can be made.

Introduction

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease, affecting approximately 1–2% of individuals over 65 years of age and constituting a growing global health burden, with ∼11.8 million prevalent cases worldwide in 2021, a strong age dependence, and male predominance (Yang et al., 2026). PD is now recognized as a multisystem disorder, encompassing not only motor disorders, such as bradykinesia, rigidity, resting tremor, and postural instability, but also a wide range of nonmotor symptoms, including depression, anxiety, sleep disturbances, and cognitive impairment (Chaudhuri et al., 2006, Sauerbier et al., 2016). The pathogenesis of PD is complex and involves ageing, environmental exposures, and gene-environment interactions (Monte, 2003, Müller-Nedebock et al., 2023). Most cases of PD are sporadic, accounting for 80–85% of all cases, while the remainder are associated with genetic mutations (Tran et al., 2020). The neuropathological hallmarks of PD include progressive loss of dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area (VTA), and widespread accumulation of misfolded α-synuclein in neuronal compartments known as Lewy bodies (Postuma et al., 2015).

Cognitive impairment, one of the most common and debilitating non-motor manifestations of PD, may precede the onset of motor symptoms by several years and involves deficits in executive function, attention, visuospatial processing, and memory (Novikov et al., 2023). Mild cognitive changes often appear in the early stages of the disease and may progress over time to PD dementia (Aarsland et al., 2001, Padovani et al., 2006). Approximately 20–25% of patients already exhibit mild cognitive impairment at the time of diagnosis, and longitudinal studies indicate that cognitive decline is a progressive process affecting the majority of patients, with a median interval of 10–15 years between motor symptom onset and dementia development (Aarsland et al., 2001, Svenningsson et al., 2012). Clinically, executive dysfunction and memory impairment are the most frequently affected domains (≈33%), followed by visuospatial deficits (≈27%) and attentional impairments (≈21%), reflecting disruption of frontostriatal, parietal, and limbic networks (Novikov et al., 2023).

The pathogenesis of cognitive impairment in PD is multifactorial, involving molecular alterations, synaptic dysfunction, and large-scale network disintegration (Novikov et al., 2023). Genetic factors contribute to vulnerability, with the APOE ε4 allele emerging as a risk factor for cognitive decline in PD and dementia with Lewy bodies, where it is associated with increased α-synuclein pathology, synaptic loss, astrogliosis, and worsened behavioral outcomes (Zenuni et al., 2023, Zhao et al., 2020). However, the impact of APOE genotype on cognition in PD appears context-dependent, varying with age, sex, disease stage, and underlying neuropathological burden (see Blazekovic et al., 2024). Beyond APOE, variability in genes such as GBA, MAPT, and SNCA has also been implicated in cognitive heterogeneity in PD, influencing disease severity, progression, and non-motor symptom profiles (Blazekovic et al., 2024, Chang et al., 2024). In parallel, impaired neuroplasticity represents a convergent mechanism underlying cognitive decline. Reduced expression of neurotrophic factors such as BDNF and EGF has been linked to PD progression and non-motor symptoms, particularly cognitive impairment, highlighting diminished neurotrophic support as a critical contributor to cognitive vulnerability (Howells et al., 2000, Lim et al., 2016, Zhao et al., 2025).

Currently, levodopa (L-DOPA), a precursor of the neurotransmitter dopamine, remains the most effective pharmacological treatment for motor symptoms of PD, as it restores the dopamine levels in the brain. However, its long-term use often results in dyskinesia, a debilitating hyperkinetic complication, and does not halt disease progression. Moreover, dopaminergic drugs (levodopa, dopamine agonists) may have potential deleterious effects on cognition (Roy et al., 2018). Surgical interventions such as deep brain stimulation may alleviate motor symptoms but also may lack disease-modifying effects (Foltynie et al., 2024, Hvingelby and Pavese, 2024). Modulation of non-motor symptoms probably requires nondopaminergic drugs. Cholinesterase and serotonin reuptake inhibitors, NMDA antagonist show only limited efficacy against non-motor symptoms (Foltynie et al., 2024, Meng et al., 2018, Zhang et al., 2020), emphasizing the urgent need for novel therapeutic approaches. Cannabinoid-based drugs may offer a promising alternative or adjunct therapy in this context.

Cannabinoids, natural compounds derived from Cannabis sativa, have attracted considerable interest for their potential to modulate various aspects of neurodegenerative diseases, including PD and Alzheimer’s disease. The class of cannabinoids includes endogenous cannabinoids (endocannabinoids, eCBs), plant-derived phytocannabinoids, and synthetic analogs. Medical interest in cannabinoids began with the isolation of their two principal active components, Δ9-tetrahydrocannabinol (THC), the primary psychoactive agent, and cannabidiol (CBD), a non-intoxicating compound (Gaoni and Mechoulam, 1964, Mechoulam and Shvo, 1963). The discovery of cannabinoid receptors (CBRs) CB1 and CB2 (Matsuda et al., 1990, Munro et al., 1993), along with their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in their synthesis and degradation (Devane et al., 1992, Mechoulam et al., 1995, Sugiura et al., 1995), led to the conceptualization of the ECS (Lu and Mackie, 2016, Piomelli, 2003). In recent years, this system has been extended into the broader definition “endocannabinoidome”, incorporating related lipid mediators, receptors, and signaling pathways (Alger, 2002, Andre et al., 2016, Di Marzo et al., 2000a).

ECS plays a critical role in maintaining the homeostasis at the cellular, tissue, and organismal levels. Within the brain, eCBs modulate neurotransmission, synaptic plasticity, neurodevelopment, and immune responses (Di Marzo, 2018). A distinctive feature of ECS signaling is its retrograde mechanism: eCBs are synthesized “on demand” in response to synaptic activity and are released from the postsynaptic neuron to act on presynaptic CB1Rs, thereby inhibiting the neurotransmitter release (Freund et al., 2003, Wilson and Nicoll, 2002). ECS-driven regulation of neurotransmitters release can modulate increased neuronal excitability in PD (Aymerich et al., 2018, Mody, 1995), making it a promising therapeutic target (Chevaleyre and Castillo, 2003). From the other hand, cannabinoids may exert anti-inflammatory effects through CB2Rs expressed on microglia and astrocytes (see Benito et al., 2008). In PD, excessive microglial activation and neuroinflammation provokes neuronal loss and correlates with cognitive deficits (Fan et al., 2015, Lindqvist et al., 2013). Targeting CB2R may restore homeostasis, dampen neuroinflammation, and protect synaptic integrity.

CB1Rs are densely expressed in brain regions relevant to cognition, including the hippocampus, prefrontal cortex, entorhinal cortex and are also abundant in certain subcortical structures, such as the dorsal striatum, amygdala, cerebellum, and substantia nigra (Bloomfield et al., 2019, Burns et al., 2007, Tsou et al., 1998). In the hippocampus, CB1Rs are predominantly localized on GABAergic terminals, where their activation induces both short-term and long-lasting suppression of inhibition, potentially enhancing the associative learning and memory consolidation (Chevaleyre and Castillo, 2003, Letzkus et al., 2015).

Along with CB1 and CB2 receptors, cannabinoids also interact with non-canonical targets, such as transient receptor potential channels (for example, TRPV1), voltage-gated ion channels, and various ligand-gated ion channels (Lin, 2021). AEA has been shown to modulate potassium, sodium, and calcium channels independently of classical cannabinoid receptors. These alternate pathways may contribute to the ECS-mediated regulation of excitability and inflammation, processes that are implicated in the pathophysiology of PD and other neurodegenerative disorders (Aymerich et al., 2018).

In a previous publication, the composition and functional significance of the ECS, together with the effects of both endogenous and exogenous cannabinoids on cognition in Alzheimer’s disease and temporal lobe epilepsy, have been discussed (Kitchigina, 2021). Based on that earlier work, this review focuses specifically on the role of cannabinoid compounds in modulating the cognitive function in PD. Here, we summarize the current experimental and clinical evidence, highlighting both the therapeutic potential and risks, and seek to clarify the sources of inconsistency in the results.

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