CBD’s potential impact on Parkinson’s disease: An updated overview

1. Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. It affects 4.5 million people worldwide, with a prevalence of 1% of the population over 60 years old; it is the second most common neurodegenerative disease [1], accounting for more than 90% of sporadic cases, and is associated with a high lifetime cost and impairment [2]. PD is generally defined as a movement disorder characterized by several common manifestations, such as abnormal posture, bradykinesia, resting tremor, and rigidity; however, other non-motor symptoms (e.g., sleep impairment, depression, and pain) are also prominent comorbidities [3].

The pathophysiology of idiopathic PD is still not fully understood, but environmental and genetic variables are known to be involved in the disease. Head injury, age, obesity, sedentary lifestyle, rural life, and herbicide/insecticide exposure have all been linked to PD in several studies; however, smokers and coffee users have a lower risk of developing PD [4]. The pathophysiology of this disease involves multiple molecular and cellular dysfunctions, including mitochondrial dysfunction, oxidative stress, alpha-synuclein misfolding and aggregation, calcium homeostasis dysregulation, and neuroinflammation [5]. These changes may result in the death of dopaminergic neurons in the nigrostriatal pathway, which is the most severe feature of PD [6].

The main standard of medical therapy to improve the symptoms of dopamine deficiency is the dopamine precursor levodopa. However, while levodopa is highly efficacious, especially when combined with DOPA decarboxylase blocking agents such as carbidopa, which inhibit the metabolic degradation of levodopa in the peripheral nervous system before it is released into the central nervous system, chronic use may lead to reduced efficacy and difficulty in titration as the therapeutic window narrows [7]. Furthermore, antiparkinsonian treatment accounts for 22–58% of the direct costs for PD patients worldwide [1]. As a result, there is an urgent need to discover more effective and tolerable alternative options with fewer side effects to slow neurodegeneration and improve patients’ quality of life.

Recently, derivatives extracted from Cannabis (Cannabis sativa L.) have attracted the focus of several studies and regulations. Apart from delta-9-tetrahydrocannabinol (Δ9-THC), which is known for its psychotropic effects, there are other non-psychotropic phytocannabinoids, and cannabidiol (CBD) is the most well-known of them because it is non-intoxicating and has several advantageous pharmacological properties. Given the growing body of literature on the clinical use of CBD, PD is one of the movement disorders of interest to researchers seeking to discover its possible therapeutic potential due to its growing popularity and favorable side effect profile [7].

In Europe, Gowers described the beneficial use of Cannabis indica tincture for treating PD for the first time in 1888. A century later, Cannabis has gained traction as a potential PD therapy [8]. Patients with PD have been found to express high levels of cannabinoid receptors (CBRs) [9]; thus, Parkinsonian models have recently been used to study the effects of the endocannabinoid system (ECS) on basal ganglia functioning and corticostriatal processing. However, there is still a lack of clinical data on the benefits of cannabinoids in patients with PD [10].

Several lines of evidence show that dopamine (DA) depletion results in a significant rearrangement of the striatal ECS. There is a strong interaction between the endocannabinoid and dopaminergic systems through specific G protein-coupled cannabinoid receptors (CB1 and CB2) in the basal ganglia. This interaction is involved in both the control of synaptic function and the regulation of motor behavior [11]. Despite progress in the molecular understanding of how cannabinoids (CBs) interact with DA, the clinical impact of CB therapies on the motor symptoms of PD is still unclear [12].

Several recent studies have investigated the role of CBD in reducing tremors and movement impairment caused by PD. According to a theory, CBD’s possible therapeutic effects in movement disorders such as PD are thought to be due to neuroprotection and a reduction in dopaminergic neuron degeneration [13].

This work presents a comprehensive review of the literature on the use of CBD in PD. The structure of this review begins with an examination of the safety and tolerability of the CBD molecule, followed by its interaction with other cannabinoids to modulate the ECS. The main objective of this review is to present essentially all the animal and clinical studies that have used CBD to treat both motor (including l-DOPA-induced dyskinesia [LID]) and non-motor symptoms of PD and highlight gaps to be filled in future research.

2. CBD: a phytocannabinoid with a pharmacological profile of interest

C. sativa plants contain more than 500 phytochemical compounds, at least 113 of which are identified as phytocannabinoids [14]. Among this mixture of phytocannabinoids, the compound that has gained attention in recent decades, in addition to Δ9-THC, is CBD, which is known as one of the main nonpsychotropic molecules of cannabis. This phytocannabinoid constitutes up to 40% of some plant extracts [2]. CBD was originally isolated in 1940 by Adams et al. [15], after which Mechoulam and Shvo determined its structure 23 years later [16]. The CBD concentration varies greatly depending on the plant’s genotype, the growing environment, and the part used to make the extract [17]. The (−) CBD isomer is the primary naturally occurring component of C. sativa. To date, CBD is recognized as a pleiotropic compound that acts on multiple targets; however, its molecular pharmacology needs to be further investigated.

In terms of CBRs, CBD has a low affinity for both CB1 and CB2 receptors [2,18,19]. According to Jones and colleagues, CBD showed no CB1 receptor agonist activity but was able to inhibit cannabinoid agonists in vitro by acting as an inverse agonist for both receptors CB1 and CB2 [20]. It also acts as an indirect agonist at CB1R by increasing endogenous levels of anandamide (AEA) via fatty acid amide hydrolase (FAAH) blockade [21,22]. CBD is thought to have no impact on how 2-AG interacts with either CB1Rs or CB2Rs [23,24]. However, CBD acts as a negative allosteric modulator of CB1R by decreasing the efficacy and potency of 2-AG at that receptor [25]. Regarding the impact of CBD on non-cannabinoid targets, it has been demonstrated that CBD acts as an agonist of transient receptor potential vanilloid channel type 2 (TRPV-2) and an antagonist of transient receptor potential for melastatin (TRPM8) [26,27]. Additionally, according to de Petrocellis et al., CBD can indirectly agonist potential vanilloid channel type 1 (TRPV-1) receptors by increasing the levels of anandamide, an endogenous agonist of TRPV-1 [21]. In terms of dopamine neurotransmission, CBD inhibits the dopaminergic receptor [28], thereby increasing endogenous levels of dopamine [29] and acting as a negative allosteric modulator of the dopaminergic receptor D2 [30]. As a result, it is suggested that CBD may have an effect on dopaminergic neurotransmission in the basal ganglia.

Under various experimental conditions, CBD reduces the production of several molecules, such as prostaglandin E2 [31], reactive oxygen species, and inducible nitric oxide synthase [13,32,33,34] and influences the production of numerous pro-inflammatory molecules [35,36,37]. The anti-inflammatory and antioxidant properties of CBD may explain most of its neuroprotective effects. Nevertheless, the specific pathways and mechanisms through which CBD exerts its effects in PD and other neurodegenerative disorders are still under investigation.

3. CBD safety and tolerability

Due to its potential medical uses, CBD is currently the focus of significant investigations, especially after the Food and Drug Administration (FDA)-approved Epidiolex^® in 2018 for the treatment of infantile refractory epilepsy syndromes (Dravet and Lennox-Gastaut). However, CBD is not completely risk-free. In preclinical research, adverse effects of CBD on animals included hypotension, changes in organ weight, decreased spermatogenesis, neurotoxicity of the central nervous system, hepatocellular damage, developmental toxicity, and embryo-fetal death, but these toxic effects were essentially observed at high doses and above-recommended levels [38]. Clinical investigations have shown that CBD can cause liver issues, diarrhea, fatigue, vomiting, somnolence, and more importantly, CBD-induced drug-drug interactions [38]. The first comprehensive review and meta-analysis of the side effects and tolerability of CBD across all medical indications revealed that only children with epilepsy were susceptible to pneumonia, respiratory depression and aspiration, sedative effect, lower appetite, and abnormal liver function. After excluding research on pediatric epilepsy, diarrhea was the sole unfavorable effect connected to CBD therapy [39]. However, while the side effects of CBD are generally less severe compared to Δ9-THC, they should not be overlooked.

In an open-label study on PD, 100 mg/mL Epidiolex^® was given to patients at doses ranging from 5 to 20–25 mg/kg per day for 10–15 days. According to the study’s findings, the side effects of Epidiolex were generally minor, and none were severe [40]. However, co-administration of clobazam with Epidiolex leads to a threefold increase in the active metabolite of clobazam, consequently increasing the risk of side effects such as excessive sedation [38]. An interesting review published in 2019 discusses CBD interactions with other drugs and the resulting side effects (for more details, see [41]). CYP450 enzymes play a crucial role in the metabolism and biotransformation of most endogenous and xenobiotic compounds. CBD has been shown to interact with several isoforms of these enzymes, including 3A4, 2C9, 2C19, 1A2, 2C8, 2B6, and 2E1 [41]. For instance, this phenomenon highlights the importance of monitoring potential drug interactions, particularly in elderly patients, where medication management is already complex and this demographic is often characterized by comorbidities, polypharmacy, and physiological changes that affect pharmacokinetics and drug tolerability [42].

According to the existing evidence from clinical trials, CBD is generally well tolerated and has few major side effects compared to Δ9-THC; nevertheless, interactions with other drugs should be carefully monitored, particularly in vulnerable populations such as the elderly and patients with chronic diseases.

4. Modulation of the ECS with cannabinoids in PD

The ECS is an endogenous system that consists of cannabinoid receptors (CB1 and CB2), their ligands (N-arachidonoyl ethanolamine [AEA or anandamide] and 2-arachidonoylglycerol [2-AG]), the enzymes that synthesize (N-arachidonoyl phosphatidyl ethanol phospholipase D [NAPE-PLD] and diacylglycerol lipase) and metabolize them (FAAH and monoacylglycerol lipase) [43]. During the course of PD, the ECS exhibits neurochemical modifications, with CB1 receptors downregulated in the early stages and upregulated (together with CB2 receptors) with a higher endocannabinoid tone in the intermediate/late stages of the disease, according to animal and human studies [44,45,46].

The preclinical research performed over the past 20 years has demonstrated that cannabinoids (both natural and synthetic) can control neurochemical changes in the glutamatergic and GABAergic systems caused by decreased dopamine levels by activating and/or inhibiting CB1/2 receptors [34,45,46,47,48]. The anatomical and functional complexity of CB1 receptors and the distribution of endocannabinoids in several subareas of the basal ganglia are also discussed in these studies. Moreover, preclinical research suggests that CB1 receptor agonists and antagonists, as well as drugs that modulate endocannabinoid metabolism, could be useful in the treatment of this disorder [34,45,46,47,48].

Several mechanisms (Figure 1) have been implicated in the action of cannabinoids in PD. These include antioxidant, anti-excitotoxic, and anti-inflammatory properties (mediated not only by activation of CB1R but also CB2R), inhibition of anandamide hydrolysis and their actions on other receptors, including modulation of the TRPV1 receptor channel and G protein-coupled receptor 55 (GPR55) among others [34,45,46,47].

Generally, cannabinoids act at two levels of basal ganglia function: glutamatergic/dopaminergic synaptic neurotransmission and corticostriatal plasticity, both of which are important in LID [10]. Additionally, activation of the ECS may result in neuroprotective effects via direct receptor-independent mechanisms [49], activation of anti-inflammatory cascades in glial cells via CB2Rs [34], and anti-glutamatergic anti-excitotoxic effects [47].

In fact, cannabinoids were shown to affect catecholaminergic and dopaminergic systems in early animal experiments [50,51]. Dopaminergic pathways, including the striatum, contain significant levels of CB1Rs, anandamide, and 2-AG, which regulate dopaminergic transmission via retrograde feedback mechanisms at presynaptic glutamate and GABAergic nerve terminals [52]. In the GABAergic system, it has been suggested that by blocking GABA uptake into the lateral part of the globus pallidus internus (GPi), cannabinoid agonists enhance GABAergic transmission in the indirect loop of the basal ganglia. In the glutamatergic system, the activation of CB1R at glutamate synapses inhibits the excitation of N-methyl-d-aspartate (NMDA) and AMPA receptors on dopamine neurons, which leads to the inhibition of excitation. Both methods may play a role in preventing dyskinesia [53].

The primary thalamo-cortical output region within the basal ganglia, particularly the medial section of the GPi, displays a high concentration of CB-1 receptors [54]. The presence of CB2Rs on human nigrostriatal dopaminergic neurons [11] shows that the ECS has direct modulatory effects on dopaminergic transmission [46]. Although nigrostriatal neurons do not express CB1R [55], they are regulated by the ECS [47,56] through CB1Rs which are expressed on GABAergic, glutamatergic, and opioidergic neurons [57]. Furthermore, interactions with various endocannabinoids have been reported for TRP channels expressed on dopaminergic neurons [58,59].

CB1R activation in the midbrain has also been shown to increase acetylcholine release, thereby ameliorating the local cholinergic deficit observed in PD [60]. Furthermore, cannabis interactions with the serotonergic system may have an impact on LID; denervation of striatal dopamine neurons causes a shift in the conversion of levodopa to dopamine from dopamine to serotonin neurons, resulting in non-physiological pulsatile dopamine release (false messengers) [61].

The concentration of CB receptors on the target structure largely determines the activating effects of a ligand with low CB receptor affinity, such as Δ9-THC. This may explain why CB ligands have such a wide range of effects, as the concentration of CB receptors varies so much in different brain areas. Moreover, the relative sensitivity of GABAergic and glutamatergic neurons to CB1-R agonists varies among species [62].

In terms of corticostriatal plasticity, experimental in vivo PD studies have shown that the ECS appears to influence corticostriatal synaptic plasticity. CB1R agonists reduce abnormal dopamine-mediated corticostriatal long-term potentiation and promote long-term depression in LID conditions, rendering glutamatergic synapses less responsive to future stimulation. This antidyskinetic effect is reversed by CB1R inhibition [46].

Investigations of PD animal models and human tissues from PD patients revealed an increase in ECS activity [63], with overexpression of CBRs [64,65], accumulation of cannabinoid receptor agonists [66,67], and a decrease in their breakdown [68]. In an animal model, chronic levodopa substitution reversed this ECS adaptation [69].

Overall, preclinical research has shown that cannabinoids can modulate the ECS, influence neurochemical changes in different systems, and potentially offer neuroprotective effects in PD. These findings suggest that ECS modulation could be a promising therapeutic approach. However, it is important to recognize that the translation of these preclinical findings to clinical practice remains uncertain.

5. Preclinical data on the use of CBD in PD

CBD has been studied extensively in preclinical investigations for a variety of neurodegenerative disorders [70]. The neuroprotective properties of CBD do not appear to depend on the direct activation of CB1 receptors [71], even though CB2 receptor involvement has been documented in specific pathological conditions [72]. The direct activity of CBD at these CBRs is still under debate. However, CBD could facilitate AEA-mediated effects by lowering FAAH activity, which is an indirect route [21].

The first preclinical study addressing CBD’s properties in PD was published by Lastres-Becker and his colleagues in 2005. The study revealed that administering 3 mg/kg CBD daily for 2 weeks reduced the depletion of dopamine and tyrosine hydroxylase in the striatum of rats injected with 6-hydroxydopamine (6-OHDA) immediately after lesion induction. The neuroprotective effect is likely mediated by cannabinoid receptor-independent antioxidant and anti-inflammatory properties [34]. However, when the treatment began one week later, there was no effect. Increased expression of Cu²⁺/Zn-superoxide dismutase mRNA, a key enzyme in endogenous oxidative stress responses, was associated with the effects of CBD [73].

In contrast, a 2016 study showed that 5 mg/kg CBD for 5 weeks did not affect dopaminergic neuron loss or motor impairments caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [74]. Another investigation in the same year tested different doses of CBD (15, 30, and 60 mg/kg, for 3 days) in a mouse model of LID by giving l-DOPA for 21 days after receiving 6-OHDA treatment. Although CBD alone had no impact, when it was combined with capsazepine (CPZ) (a TRPV-1 antagonist) at a dose of 30 mg/kg, it resulted in a remarkable reduction in involuntary movements induced by l-DOPA. Furthermore, this combination significantly reduced the levels of the pro-inflammatory markers cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-κB). CB1 and peroxisome proliferator-activated type gamma (PPAR) receptor antagonists prevented all of these effects. Thus, the anti-inflammatory effects mediated by CB1 and PPAR receptors are thought to be responsible for the neuroprotective effects of CBD (when combined with a TRPV-1 antagonist) [75]. CB2R activation, but not CB1R activation, may have neuroprotective effects on PD, which could be due to an anti-inflammatory effect [64,73]. CB2R agonists protected mice from MPTP-induced nigrostriatal degeneration by decreasing microglial activation and infiltration, according to rodent PD model research [76]. More recently, Wang and colleagues have demonstrated that the administration of 100 mg/kg CBD by oral gavage for 14 days alleviates PD symptoms in the MPTP mouse model. The study reported an improvement of cognitive behaviors, an increase in DA, 5-HT, and IL-10 levels, and a decrease in several apoptosis and neuroinflammation markers [77].

Drug-induced catalepsy tests, which are often used to assess motor deficits due to changes in striatal function, were employed in two investigations [78,79]. The first study aimed to test the effects of acute CBD pretreatment (5, 15, 30, or 60 mg/kg) on catalepsy caused by haloperidol (a D2 receptor antagonist), l-nitro-N-arginine (a selective nitric oxide synthase [NOS] inhibitor), and WIN55,212 (a CB1 receptor agonist) in male Swiss mice. CBD reduced the increase in catalepsy time caused by all three medications in a dose-dependent manner [78]. In the second study, rats were given reserpine (an irreversible inhibitor of vesicular monoamine transporters 1 and 2 or VMAT1/2) to cause motor impairments and cognitive abnormalities to imitate both tardive dyskinesia and PD. In the discriminative avoidance task, CBD doses of 0.5 or 5 mg/kg considerably reduced reserpine-induced catalepsy and chewing movements (but not locomotor activity), and the lowest dose also significantly improved reserpine-induced memory/learning deficits [79].

CBD has been shown to protect neurons in both cell tissue and animal models of PD in vitro. CBD enhanced the survival, differentiation, and expression of axons (GAP-43) and the synaptic proteins synaptophysin and synapsin I in a cellular model of PD in PC12 and SH-SY5Y cells treated with 1-methyl-4-phenylpyridinium (MPP+) [80]. After incubation with lipopolysaccharide (LPS), CBD enhances cell viability and decreases microglial activation [81,82]. Since chronic inflammation is a prominent hallmark of PD and dopaminergic neurons are particularly sensitive to glial activation [83], the anti-inflammatory properties of CBD may contribute to its neuroprotective potential in PD [2]. In a cell culture model of PD, differentiated SH-SY5Y neuroblastoma cells were exposed to three toxins that model PD-associated biochemical abnormalities: reduced mitochondrial activity by MPP+, free radical production by paraquat, and inhibition of the ubiquitin‒proteasome system by lactacystin. MPP+ and lactacystin administration resulted in substantial upregulation of CB1 receptors. In this model, no protective effects of CBD (0.01–1.0 M) were identified [49].

In these animal and cellular models of motor, biochemical, and cognitive symptoms, the preclinical data discussed above suggest that CBD generally alleviates PD-related symptoms. However, the majority of studies have employed a single model of motor symptoms, with only a few examining additional elements of PD. Furthermore, the overall volume of investigations is still limited, and their methodology varies in terms of CBD dosage.

6. Clinical trials on the use of CBD in PD

To date, 17 clinical studies using Cannabis or its derivatives to treat PD have been reported in the literature (Appendix). Seven studies utilized CBD as the main drug of interest, six studies used pure CBD [60,84,85,86,87,88], and one study used a mixture of 1.25 mg CBD and 2.5 mg Δ9-THC (Cannador^®) [89].

7. Effects of CBD on LID

8. Conclusion

The above-cited preclinical studies collectively suggest that CBD is a promising candidate for the treatment of various health conditions which is due to the fact that it lacks psychoactive effects and is a potent anti-inflammatory and antioxidant compound. In the context of clinical trials, it is challenging to derive definitive conclusions about the efficacy of CBD as a treatment for PD, given that only seven studies have been conducted thus far. Nevertheless, the current body of research is constrained by several limitations. A notable limitation is the insufficient number of large-scale, high-quality randomized controlled trials examining the efficacy and safety of CBD in the treatment of PD. The majority of existing studies are relatively small and have various methodological shortcomings, with considerable heterogeneity in terms of study design, CBD dosages, routes of administration, and outcome measures. Furthermore, the majority of patients diagnosed with PD are of an advanced age. Consequently, age-related factors, including comorbidities, polypharmacy, and alterations in pharmacokinetics and pharmacodynamics, can potentially impact the efficacy of CBD treatment. Moreover, the impact of sex differences on the effectiveness and safety of CBD has not been sufficiently explored, and male and female patients may exhibit variability in their response to treatment. Additionally, many studies do not stratify results based on disease stage, which limits the ability to ascertain the efficacy of CBD at different stages of the disease.

To address the aforementioned limitations, it is proposed that several avenues for future investigation be explored. The necessity for large-scale, double-blind, placebo-controlled trials is paramount for the evaluation of the efficacy of CBD in treating both motor and non-motor symptoms of PD. Longitudinal studies are essential to investigate the long-term effects of CBD on human health, including an assessment of its safety, efficacy, and potential disease-modifying properties. The establishment of standardized protocols for CBD dosage, administration routes, and outcome measures will facilitate greater comparability between studies and help to reduce heterogeneity. To gain a deeper understanding of the mechanisms through which CBD interacts with the ECS and other neurotransmitter systems in the context of neurodegenerative disorders, further mechanistic studies are required. An investigation into the potential advantages of combining CBD with other pharmacological interventions, such as l-DOPA, may elucidate synergistic effects that could enhance therapeutic efficacy. Furthermore, future studies should concentrate on age-specific analyses to address age-related factors and guarantee applicability to the typical demographic affected by PD. It would be beneficial to include sex-based analyses to identify any differential effects of CBD between male and female patients. Ultimately, stratifying patients based on the stages of PD will facilitate the determination of the efficacy and safety of CBD at various stages of disease progression, thereby providing more precise guidance for its use in clinical practice.

Notably, due to CBD’s well-documented safety profile in patients, it may represent a promising add-on therapy with the potential to alleviate some symptoms. Accordingly, we believe that more extensive, well-designed preclinical and clinical research addressing motor and non-motor symptoms of this disease is required to establish the true effects of CBD.

Abbreviations

ABC

Activities of balance confidence

ADL scale

Activities of daily living

BAI

Beck Anxiety Inventory

BDNF

Brain-derived neurotrophic factor

BPRS

Brief Psychiatric Rating Scale

CGI-I

Clinical Global Impression Improvement

ESS

Epworth Sleepiness Scale

FAB

Frontal assessment battery

FSS

Fatigue Severity Scale

GNDS

Guy’s Neurological Status Scale

IPAQ

International Physical Activities Questionnaire

H1-MRS

Proton magnetic resonance scans

H&Y scale

Hoehn & Yahr

LID

(l-DOPA)-induced dyskinesias

MMSE

Mini-mental status examination

NHP

Nottingham Health Profile

NR

Nonreported

NSAID

Nonsteroidal anti-inflammatory drug

PAS

Parkinson Anxiety Scale

PDQ-39

Parkinson’s Disease Questionnaire-39

PPQ

Parkinson Psychosis Questionnaire

PRI

Pain Rating Index

PSQI

Pittsburgh Sleep Quality Index

PSS

PD Sleep Scale

RBD

Rapid eye movement sleep behavior disorder

RBDSQ

REM Sleep Behavior Disorder Screening Questionnaire

RLS

Restless leg syndrome

SDS

Zung Self-Rating Depression Scale

SPST

Simulated Public Speaking Test

SSPS

Self- Statements during Public Speaking Scale

THC

Tetrahydrocannabinol

UPDRS

Unified Parkinson Disease Rating Scale

UKU

Udvalg for kliniske undersøgelser

VAS

Visual Analog Scale

VAMS

Visual Analog Mood Scales